EP4313967A1 - Khk inhibitors - Google Patents

Khk inhibitors

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Publication number
EP4313967A1
EP4313967A1 EP22719399.2A EP22719399A EP4313967A1 EP 4313967 A1 EP4313967 A1 EP 4313967A1 EP 22719399 A EP22719399 A EP 22719399A EP 4313967 A1 EP4313967 A1 EP 4313967A1
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EP
European Patent Office
Prior art keywords
alkyl
aryl
cycloalkyl
haloalkyl
heteroaryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22719399.2A
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German (de)
English (en)
French (fr)
Inventor
James L. Bachman
Daniel H. BYUN
Christopher T. Clark
Petr Jansa
Joshua A. Kaplan
Zachary A. KASUN
Jennifer R. Lo
Megan E. NEUBIG
Nathaniel H. STANLEY
Kirk L. Stevens
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Gilead Sciences Inc
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Gilead Sciences Inc
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Application filed by Gilead Sciences Inc filed Critical Gilead Sciences Inc
Publication of EP4313967A1 publication Critical patent/EP4313967A1/en
Pending legal-status Critical Current

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems
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    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • BACKGROUND Excess fructose is linked with the development of insulin resistance, hyperglycemia and with several comorbidities associated with diabetes and metabolic syndrome, including: non- alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), liver disease, liver fibrosis, metabolic syndrome, obesity, hyperlipidemia, hypertriglyceridemia, hypertension, fibrosis, steatosis, cirrhosis, cardiometabolic syndrome, insulin resistance, cardiovascular disease, heart failure, type 1 and type 2 diabetes mellitus, chronic kidney disease (CKD), diabetic kidney disease (DKD), kidney disease, kidney fibrosis, kidney insufficiency, irritable bowel syndrome disease (IBD), ulcerative colitis, Crohn's disease, hyperuricemia, gout, diseases driven by inflammasome activation, arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis or cancer (
  • fructose is also endogenously produced during cellular stress, injury, tissue damage or increased glucose concentrations among others. This endogenous fructose production occurs through the polyol pathway in in the liver, intestines, and kidney where it contributes to exacerbation of injury and metabolic dysfunction (Andres-Hernando et al., 2017; Lanaspa et al., 2013).
  • fructose-1-phosphate F1P
  • F1P fructose-1-phosphate
  • fructose-1- phosphate F1P
  • glyceraldehyde glyceraldehyde
  • dihydroxyacetone phosphate methylglyoxal
  • methylglyoxal adenosine triphosphate
  • Ketohexokinase is the primary and rate-limiting enzyme for both dietary and endogenous fructose metabolism, and therefore represents a promising drug target for pharmacological intervention in diseases where fructose and the polyol pathway contribute to metabolic disease and associated comorbidities.
  • KHK is expressed as two major mRNA splice variants.
  • KHK mRNA variant 3C is preferentially expressed in the small intestine (enterocytes), liver (hepatocytes) and kidney (proximal tubule cells) (Diggle et al., 2009; Hayward & Bonthron, 1998). These organs metabolize the majority of dietary and endogenously produced fructose.
  • An alternative splice variant of KHK (variant 3A, isoform-A, KHK-A) is expressed more ubiquitously in other organs, including, but not limited to heart, brain and skeletal muscle. KHK catalyzes the ATP-dependent conversion of fructose to F1P.
  • KHK-C Increased metabolism of fructose by KHK-C causes accumulation of F1P and uric acid, and rapid ATP depletion.
  • KHK-C has a higher affinity for fructose than KHK-A and results in a more rapid metabolism of fructose than KHK-A.
  • neither KHK-A or KHK-C are subject to negative feedback inhibition or allosteric regulation, therefore, fructose is immediately, and continually metabolized by KHK (Ishimoto et al., 2012).
  • ALDOB is the enzyme immediately downstream of KHK and is responsible for the conversion of F1P to dihydroxy acetone phosphate (DHAP) and Glyceraldehyde phosphate (GAP). Defects in ALDOB result in accumulation of F1P, ATP depletion and increased uric acid.
  • HFI is a rare disorder and its prevalence is approximately 1 in 20,000 people (Simons et al., 2019). Individuals with HFI are severely intolerant to dietary fructose and demonstrate acute symptoms like vomiting, hypoglycemia, diarrhea and abdominal distress.
  • EF essential fructosuria
  • KHK-A/C homozygous knockout mice appear normal and healthy and excrete excess fructose in the urine, similar to humans with EF. Additionally, KHK-A/C null mice are protected from features of liver and kidney disease such as kidney tubular cell injury, inflammation, liver steatosis and fibrosis (Andres-Hernando et al., 2017; Lanaspa et al., 2013).
  • KHK inhibitors There are currently two classes of known KHK inhibitors, and both utilize the presence of a charged residue for potency and/or metabolic stability and/or acceptable pharmacokinetic properties.
  • Acyl glucuronide metabolites can be chemically reactive leading to covalent binding with macromolecules and cumulative toxicity (Vleet Van et al., Toxicology Letters, 2017, 272, 1-7).
  • Compounds containing carboxylic acids tend to be substrates for the organic anion transporter (OAT) family encoded by SLC22A, the organic anion transporting peptide (OATP) family encoded by SLC21A (SLCO), and the multidrug resistance-associated protein (MRP) family encoded by ABCC (Sekine et al., Am. J. Physiol. Renal Physiol., 2006, 290, F251–F261). This can lead to asymmetric tissue exposure (i.e.
  • tissue accumulation via active uptake and reduced tissue exposure via active efflux can represent a risk specific to KHK-C inhibitors where higher KHK-C inhibition in one organ may lead to higher circulating fructose concentrations in plasma which may lead to enhanced KHK-C mediated fructose metabolism (and subsequent enhanced ATP depletion and tissue damage) in an organ with reduced or lower inhibitor concentration (free drug concentration).
  • Carboxylic acids tend to be not only substrates but also inhibitors of OATPs leading to drug-drug interactions (DDI) with some essential medications (Kalliokoski et al., Br. J.
  • Basic amines are well known for their higher risk of promiscuity or lack of biological selectivity or safety risks such as hERG inhibition or phospholipidosis, inter-organ variation in exposures since basic drugs tend to be stored in tissues with a pH that is lower than their pKa values e.g., lung.
  • Basic amine containing compounds often become sequestered in acidic organelles of many different cell types and may thereby contribute to various toxicities and additionally be metabolized to form reactive iminium species (Yukawa et al., ACS Med. Chem. Lett., 2020, 11, 203-209; Charifson et al., J. Med. Chem., 2014, 57, 9701-9717).
  • KHK inhibitors with advantageous properties, for example: equal tissue distribution, high target engagement and good pharmacokinetics properties. While progress has been made, there is still a need for more potent, novel KHK inhibitors with low tissue asymmetry, low drug-drug interaction liability, reduced off target liability and minimal toxicity. References: Aldamiz-Echevarria, L., de Las Heras, J., Couce, M. L., Alcalde, C., Vitoria, I., Bueno, M., ... Villate, O. (2020).
  • the present disclosure provides a compound of Formula I Formula I or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is a 4-10 membered heterocyclic moiety, wherein the heterocycle contains 1-3 heteroatoms, and is optionally substituted with up to four R 1a ; or C 3-7 cycloalkyl, optionally substituted with up to four substituents independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, halogen, CN, OH, CH 2 OH, CH 2 OR 11 , CONH 2 , CONHR 11 , NHCOR 13 SO 2 NH 2 , SO 2 NHR 11 , NHSO 2 R 13 or oxo; each R 1a is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, OH, OR 1b , CH 2 OH,
  • the present disclosure provides a compound of Formula I, Formula I or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is a 4-10 membered heterocyclic moiety, wherein the heterocycle contains 1-3 heteroatoms, and is optionally substituted with up to four R 1a ; or C 3-7 cycloalkyl, optionally substituted with up to four substituents independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, halogen, CN, OH, CH 2 OH, CH 2 OR 11 , CONH 2 , CONHR 11 , NHCOR 13 , SO 2 NH 2 , SO 2 NHR 11 , NHSO 2 R 13 or oxo; each R 1a is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, OH, OR 1b , CH 2 OH, COOH, CO 2 R 12 , halogen, oxo, CONH 2 , CN
  • each R 1a is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, OH, OR 1b , CH 2 OH, COOH, CO 2 R 12 , halogen, oxo, CONH 2 , CN, NH 2 , NHR 11 , C 1-6 alkyl-NHSO 2 R 13 , C 1-6 alkyl-NHCOR 13 , C 1-6 alkoxy or C 1-6 haloalkyl, wherein the alkyl, alkenyl, or alkynyl are optionally substituted with up to three R 1c , alternatively two R 1a can be combined with the atoms to which they are attached to form a 3-6 membered spiro, fused or bridged ring; R 1b is H, or C 1-6 alkyl, wherein the alkyl is optionally substituted with up to three halogens,
  • the present disclosure provides a compound of Formula V, Formula V wherein R 1 is a 4-10 membered heterocyclic moiety, wherein the heterocycle contains 1-3 heteroatoms, and is optionally substituted with up to four R 1a ; or C 3-7 cycloalkyl, optionally substituted with up to four substituents independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, halogen, CN, OH, CH 2 OH, CH 2 OR 11 , CONH 2 , CONHR 11 , NHCOR 13 , SO 2 NH 2 , SO 2 NHR 11 , NHSO 2 R 13 or oxo; each R 1a is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, OH, OR 1b , CH 2 OH, CO 2 R 12 , halogen, oxo, CONH 2 , CN, NH 2 , N
  • the present disclosure provides a compound of Formula V, Formula V or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is a 4-10 membered heterocyclic moiety, wherein the heterocycle contains 1-3 heteroatoms, and is optionally substituted with up to four R 1a ; or C 3-7 cycloalkyl, optionally substituted with up to four substituents independently selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, halogen, CN, OH, CH 2 OH, CH 2 OR 11 , CONH 2 , CONHR 11 , NHCOR 13 , SO 2 NH 2 , SO 2 NHR 11 , NHSO 2 R 13 or oxo; each R 1a is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, OH, OR 1b , CH 2 OH, COOH, CO 2 R 12 , halogen, oxo, CONH 2 , CN
  • Alkyl is a linear or branched saturated monovalent hydrocarbon.
  • an alkyl group can have 1 to 18 carbon atoms (i.e., C1-18 alkyl) or 1 to 8 carbon atoms (i.e., C1-8 alkyl) or 1 to 6 carbon atoms (i.e., C 1-6 alkyl) or 1 to 4 carbon atoms (i.e., C 1-4 alkyl).
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, - CH 2 CH 2 CH 2 CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH 2 CH(CH3)2), 2-butyl (s-Bu, s- butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n- pentyl, -CH 2 CH 2 CH 2 CH3), 2-pentyl (-CH(CH3)CH 2 CH 2 CH3), 3-
  • alkyl groups include heptyl, octyl, nonyl, decyl, undecyl, dodecyl, pentadcyl, hexadecyl, heptadecyl and octadecyl.
  • Alkenyl is a monovalent or divalent linear or branched hydrocarbon radical with at least one carbon-carbon double bond.
  • an alkenyl group can have 2 to 8 carbon atoms (i.e. C2-8 alkenyl) or 2 to 6 carbon atoms (i.e. C2-6 alkenyl) or 2 to 4 carbon atoms (i.e. C2-4 alkenyl).
  • Alkenyl groups can be unsubstituted or substituted.
  • Alkynyl is a monovalent or divalent linear or branched hydrocarbon radical with at least one carbon-carbon triple bond.
  • an alkynyl group can have 2 to 8 carbon atoms (i.e. C 2-8 alkynyl) or 2 to 6 carbon atoms (i.e. C 2-6 alkynyl) or 2 to 4 carbon atoms (i.e. C 2- 4 alkynyl).
  • alkynyl groups examples include, but are not limited to, acetylenyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), and –CH 2 -C ⁇ C-CH3.
  • Alkynyl groups can be unsubstituted or substituted.
  • Alkoxy refers to an alkyl group having an oxygen atom that connects the alkyl group to the point of attachment: alkyl-O-.
  • alkyl group alkoxy groups can have any suitable number of carbon atoms, such as C1-6.
  • Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, OCF 3 , OCHF 2 , etc.
  • Aryl refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic.
  • an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms.
  • Aryl includes a phenyl radical.
  • Aryl also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., carbocycle).
  • Such multiple condensed ring systems are optionally substituted with one or more (e.g., 1, 2 or 3) oxo groups on any carbocycle portion of the multiple condensed ring system.
  • the rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements.
  • aryl e.g., 6-10 membered aryl
  • the atom range is for the total ring atoms of the aryl.
  • a 6-membered aryl would include phenyl and a 10-membered aryl would include naphthyl and 1,2,3,4-tetrahydronaphthyl.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4- tetrahydronaphthyl, anthracenyl, and the like.
  • polycyclic carbocycles include, without limitation: or “Cycloalkyl” refers to a single saturated or partially unsaturated all carbon ring having 3 to 20 annular carbon atoms (i.e., C3-20 cycloalkyl), for example from 3 to 12 annular atoms, for example from 3 to 10 annular atoms, or 3 to 8 annular atoms, or 3 to 6 annular atoms, or 3 to 5 annular atoms, or 3 to 4 annular atoms.
  • the term “cycloalkyl” also includes multiple condensed, saturated and partially unsaturated all carbon ring systems (e.g., ring systems comprising 2, 3 or 4 carbocyclic rings).
  • cycloalkyl includes multicyclic carbocycles such as a bicyclic carbocycles (e.g., bicyclic carbocycles having 6 to 12 annular carbon atoms such as bicyclo[3.1.0]hexane, bicyclo[2.2.1]heptane and bicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g., tricyclic and tetracyclic carbocycles with up to 20 annular carbon atoms).
  • the rings of a multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements.
  • Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1- enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl and 1-cyclohex-3-enyl.
  • Alkyl-cycloalkyl refers to a radical having an alkyl component and a cycloalkyl component, where the alkyl component links the cycloalkyl component to the point of attachment.
  • the alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the cycloalkyl component and to the point of attachment. In some instances, the alkyl component can be absent.
  • the alkyl component can include any number of carbons, such as C 1-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 .
  • the cycloalkyl component is as defined within.
  • alkyl-cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methyl- cyclopentyl and methyl-cyclohexyl.
  • Alkyl-aryl refers to a radical having an alkyl component and an aryl component, where the alkyl component links the aryl component to the point of attachment.
  • the alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to link to the aryl component and to the point of attachment. In some instances, the alkyl component can be absent.
  • the alkyl component can include any number of carbons, such as C1-6, C1-2, C1-3, C1-4, C1-5, C2-3, C2-4, C2-5, C2-6, C3-4, C3-5, C3-6, C4-5, C4-6 and C5-6.
  • the aryl component is as defined herein.
  • Exemplary alkyl-aryl groups include, but are not limited to, methyl-phenyl, or ethyl-phenyl.
  • Heterocyclyl or “heterocycle” or “heterocycloalkyl” or “heterocyclic” as used herein refers to a single saturated or partially unsaturated non-aromatic ring or a multiple ring system having at least one heteroatom in the ring (i.e., at least one annular heteroatom selected from oxygen, nitrogen, and sulfur) wherein the multiple ring system includes at least one non- aromatic ring containing at least one heteroatom.
  • the multiple ring system can also include other aromatic rings and non-aromatic rings.
  • a heterocyclyl group has from 3 to 20 annular atoms, for example from 3 to 12 annular atoms, for example from 3 to 10 annular atoms, or 3 to 8 annular atoms, or 3 to 6 annular atoms, or 3 to 5 annular atoms, or 4 to 6 annular atoms, or 4 to 5 annular atoms.
  • the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) having from 1 to 6 annular carbon atoms and from 1 to 3 annular heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring.
  • the rings of the multiple condensed ring (e.g. bicyclic heterocyclyl) system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements.
  • Heterocycles include, but are not limited to, azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-1- azaspiro[3.3]heptan-1-yl, 2-thia-6-azaspiro[3.3]heptan-6-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2- azabicyclo[3.1.0]hexan-2-yl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[2.1.1
  • C1-4 haloalkyl is a C1-4 alkyl wherein one or more of the hydrogen atoms of the C1-4 alkyl have been replaced by a halo substituent.
  • haloalkyl groups include but are not limited to fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and pentafluoroethyl.
  • Heteroaryl refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; “heteroaryl” also includes multiple condensed ring systems that have at least one such aromatic ring, which multiple condensed ring systems are further described below. Thus, “heteroaryl” includes single aromatic rings from 1 to 6 carbon atoms and 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic.
  • heteroaryl ring systems include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl.
  • “Heteroaryl” also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined above, is condensed with one or more rings selected from heteroaryls (to form for example 1,8-naphthyridinyl), heterocycles, (to form for example 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycles (to form for example 5,6,7,8-tetrahydroquinolyl) and aryls (to form for example indazolyl) to form the multiple condensed ring system.
  • heteroaryls to form for example 1,8-naphthyridinyl
  • heterocycles to form for example 1,2,3,4-tetrahydro-1,8-naphth
  • a heteroaryl (a single aromatic ring or multiple condensed ring system) has 1-20 carbon atoms and 1-6 heteroatoms within the heteroaryl ring.
  • Such multiple condensed ring systems may be optionally substituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on the carbocycle or heterocycle portions of the condensed ring.
  • the rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another.
  • the point of attachment for a heteroaryl or heteroaryl multiple condensed ring system can be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system including a carbon atom and a heteroatom (e.g., a nitrogen).
  • a heteroatom e.g., a nitrogen
  • the atom range is for the total ring atoms of the heteroaryl and includes carbon atoms and heteroatoms.
  • a 5-membered heteroaryl would include a thiazolyl and a 10-membered heteroaryl would include a quinolinyl.
  • heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8- tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, and triazolyl.
  • Heteroaryl rings also include 8 to 15 membered fused rings having 2, 3, or more rings wherein at least one ring is an aromatic ring and at least one ring is a non-aromatic ring containing at least one heteroatom.
  • Representative fused bicyclic heteroaryls include, but are not limited to, indoline (dihydroindole), isoindoline (dihydroisoindole), indazoline (dihydroindazole), benzo[d]imidazole, dihydroquinoline, dihydroisoquinoline, dihydrobenzofuran, dihydroisobenzofuran, benzo[d][1,3]dioxol, dihydrobenzo[b]dioxine, dihydrobenzo[d]oxazole, dihydrobenzo[b]thiophene, dihydroisobenzo[c]thiophene, dihydrobenzo[d]thiazole, dihydrobenz
  • each R 2a is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, SO 2 R 2c , SOR 2c , SO 2 NH 2 , COOH, CO 2 R 12 , CONH 2 , COR 2c , CONHR 2e , CON(R 2c ) 2 , halogen, oxo, OH, CN, NH 2 , NHR 2c , N(R 2c ) 2 , NHCOR 2c , N(R 2c )COR 2c , NO 2 , SO 2 NHR 2c , SO 2 N(R 2c )2, NHSO 2 R 2c , N(R 2c )SO 2 R 2c , S(O)(NH)R 2c , S(O)(NH)NH 2 , NHS(O)
  • heteroaryl groups include, without limitation:
  • a “compound of the present disclosure” includes compounds disclosed herein, for example a compound of the present disclosure includes compounds of Formulas (I-VI).
  • Composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product, which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and deleterious to the recipient thereof.
  • “Pharmaceutically effective amount” refers to an amount of a compound of the present disclosure in a formulation or combination thereof, that provides the desired therapeutic or pharmaceutical result.
  • Treatment or “treat” or “treating” as used herein refers to an approach for obtaining beneficial or desired results.
  • beneficial or desired results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom and/or preventing a worsening of a symptom associated with a disease or condition.
  • treatment includes one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); and c) relieving the disease or condition, e.g., causing the regression of clinical symptoms, ameliorating the disease state, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.
  • inhibiting the disease or condition e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition
  • slowing or arresting the development of one or more symptoms associated with the disease or condition e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition
  • relieving the disease or condition e.g., causing the regression of
  • “Therapeutically effective amount” or “effective amount” as used herein refers to an amount that is effective to elicit the desired biological or medical response, including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the effective amount can vary depending on the compound, the disease, and its severity and the age, weight, etc., of the subject to be treated.
  • the effective amount can include a range of amounts.
  • an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint.
  • an effective amount may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.
  • administering refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to the subject.
  • Co-administration refers to administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration of the compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents.
  • a unit dose of a compound of the present disclosure is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents.
  • a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound of the present disclosure within seconds or minutes.
  • a unit dose of a compound of the present disclosure is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents.
  • a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound of the present disclosure.
  • Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of each agent are present in the body of the patient.
  • Subject refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In certain embodiments, the subject is a human.
  • Disease or “condition” refer to a state of being or health status of a patient or subject capable of being treated with a compound, pharmaceutical composition, or method provided herein. Provided are also pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein.
  • “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.
  • the compounds of described herein may be prepared and/or formulated as pharmaceutically acceptable salts or when appropriate as a free base.
  • Pharmaceutically acceptable salts are non-toxic salts of a free base form of a compound that possesses the desired pharmacological activity of the free base. These salts may be derived from inorganic or organic acids or bases. For example, a compound that contains a basic nitrogen may be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid.
  • Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates
  • salts derived from an appropriate base such as an alkali metal (for example, sodium, potassium), an alkaline earth metal (for example, magnesium), ammonium and NX4 + (wherein X is C 1 ⁇ C 4 alkyl).
  • base addition salts such as sodium or potassium salts.
  • n is the number of hydrogen atoms in the molecule.
  • the deuterium atom is a non-radioactive isotope of the hydrogen atom.
  • Such compounds may increase resistance to metabolism, and thus may be useful for increasing the half-life of the compounds described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof when administered to a mammal. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol.
  • Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.
  • isotopes that can be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, respectively.
  • Isotopically-labeled compounds of Formulas (I-VI) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • the compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.
  • the present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • chirality is not specified but is present, it is understood that the embodiment is directed to either the specific diastereomerically or enantiomerically enriched form; or a racemic or scalemic mixture of such compound(s).
  • scalemic mixture is a mixture of stereoisomers at a ratio other than 1:1.
  • Racemates refers to a mixture of enantiomers. The mixture can comprise equal or unequal amounts of each enantiomer.
  • Stepoisomer and “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
  • the compounds may exist in stereoisomeric form if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see, e.g., Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).
  • a wavy line drawn through a line in a structure indicates a point of attachment of a group.
  • a dashed line indicates an optional bond.
  • no directionality is indicated or implied by the order in which a chemical group is written or the point at which it is attached to the remainder of the molecule.
  • the group “-SO 2 CH 2 -” is equivalent to “-CH 2 SO 2 -” and both may be connected in either direction.
  • an “arylalkyl” group for example, may be attached to the remainder of the molecule at either an aryl or an alkyl portion of the group.
  • a prefix such as “Cu-v” or (Cu-Cv) indicates that the following group has from u to v carbon atoms.
  • C1-6alkyl and C1-C6 alkyl both indicate that the alkyl group has from 1 to 6 carbon atoms.
  • Solvate refers to the result of the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.
  • the compounds of the present disclosure can be prepared by any method known in the art.
  • the following exemplary general methods illustrate routes that were used to obtain a compound of the present disclosure.
  • compounds of Formula 13 were prepared from commercially available or literature known compounds of Formula 1, wherein LG 1 or LG 2 are leaving groups, typically, but not limited to, halides or sulfones.
  • Treatment of compounds of Formula 1 with an appropriate R 2 -M (4), with or without the presence of catalyst(s), and with or without the presence of base(s) gave compounds of Formula 2 through cross coupling reaction.
  • M groups that are suitable are, but not limited to, -B(OH)2, -B(pin), -Sn(alkyl)3, -ZnX, or -MgX.
  • Functional groups on R 2 may require protection with appropriate protecting groups, as determined by one skilled in the art.
  • Catalysts for this transformation were often, but not limited to Pd(PPh3)4, Pd(dppf)Cl2, Pd(OAc)2, PdCl2 Pd XPhos G1, G2, G3, or G4 precatalysts, Pd SPhos G1, G2, G3, or G4 precatalysts, or Pd 2 dba 3 with or without phosphine ligands, selected from, but not limited to, SPhos, XPhos, RuPhos, XantPhos, PCy 3 , PPh 3 , or dppf.
  • Bases for this transformation were, but not limited to, sodium carbonate, potassium carbonate, cesium carbonate, tribasic potassium phosphate, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate, cesium fluoride, triethyl amine, diisopropylethyl amine, or pyridine.
  • Compounds of Formula 2 were treated with nucleophile H-R 1 in the presence of base in the instances where R 1 was an amine to give compounds of Formula 13.
  • H-R 1 or M-R 1 with compounds of Formula 2 were used in the presence of a catalyst and/ or base to afford compounds of Formula 13.
  • Catalysts and bases were, but not limited to, those described above.
  • R 1 may require protection with appropriate protecting groups, as determined by one skilled in the art.
  • Scheme 1 M-R 2 (4) compounds that were not commercially available or literature known were typically derived from the corresponding halide 3 through activation with a catalyst in the presence of a base and appropriate reagents for generating nucleophiles (Scheme 2). Catalyst and bases were, but not limited to, those listed above. Reagents to generate nucleophiles were, but not limited to, B2pin2 or Sn2(alkyl)6. Often, but not always, compounds of Formula 4 were used directly in a one-pot cross coupling with compounds of Formula 2 to give compounds of Formula 13.
  • the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure (e.g. a compound of Formula I-VI), or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises a compound of Formulas (I-VI), or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more additional therapeutic agents, as more fully set forth below.
  • Pharmaceutical compositions comprising the compounds disclosed herein, or pharmaceutically acceptable salts or stereoisomers thereof may be prepared with one or more pharmaceutically acceptable excipients which may be selected in accord with ordinary practice.
  • Tablets may contain excipients including glidants, fillers, binders and the like.
  • Aqueous compositions may be prepared in sterile form, and when intended for delivery by other than oral administration generally may be isotonic.
  • compositions may contain excipients such as those set forth in the Rowe et al, Handbook of Pharmaceutical Excipients, 6 th edition, American Pharmacists Association, 2009. Excipients can include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
  • the composition is provided as a solid dosage form, including a solid oral dosage form.
  • compositions include those suitable for various administration routes, including oral administration.
  • the compositions may be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient (e.g., a compound of the present disclosure or a pharmaceutical salt thereof) with one or more pharmaceutically acceptable excipients.
  • the compositions may be prepared by uniformly and intimately bringing into association the active ingredient with liquid excipients or finely divided solid excipients or both, and then, if desired, shaping the product. Techniques and formulations generally are found in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.
  • compositions described herein that are suitable for oral administration may be presented as discrete units (a unit dosage form) including but not limited to capsules, sachets or tablets each containing a predetermined amount of the active ingredient.
  • the pharmaceutical composition of the disclosure is a tablet.
  • Pharmaceutical compositions disclosed herein comprise one or more compounds disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, together with a pharmaceutically acceptable excipient and optionally other therapeutic agents.
  • Pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more excipients including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets are acceptable.
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate
  • granulating and disintegrating agents such as maize starch, or alginic acid
  • a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • the amount of active ingredient that may be combined with the inactive ingredients to produce a dosage form may vary depending upon the intended treatment subject and the mode of administration.
  • a dosage form for oral administration to humans may contain approximately 1 to 1000 mg of active material formulated with an appropriate and convenient amount of a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient varies from about 5 to about 95% of the total compositions (weight:weight).
  • compositions comprising a compound of the present disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof in one variation does not contain an agent that affects the rate at which the active ingredient is metabolized.
  • compositions comprising a compound of the present disclosure in one aspect do not comprise an agent that would affect (e.g., slow, hinder or retard) the metabolism of a compound of the present disclosure or any other active ingredient administered separately, sequentially or simultaneously with a compound of the present disclosure.
  • any of the methods, kits, articles of manufacture and the like detailed herein in one aspect do not comprise an agent that would affect (e.g., slow, hinder or retard) the metabolism of a compound of the present disclosure or any other active ingredient administered separately, sequentially or simultaneously with a compound of the present disclosure.
  • the pharmaceutical compositions described above are for use in a human or an animal.
  • the disclosure further includes a compound of the present disclosure for administration as a single active ingredient of a pharmaceutically acceptable composition which can be prepared by conventional methods known in the art, for example by binding the active ingredient to a pharmaceutically acceptable, therapeutically inert organic and/or inorganic carrier or excipient, or by mixing therewith.
  • a compound of the present disclosure as a second or other active ingredient having a synergistic effect with other active ingredients in known drugs, or administration of the compound of the present disclosure together with such drugs.
  • a compound of the present disclosure may also be used in the form of a prodrug or other suitably modified form which releases the active ingredient in vivo. ROUTES OF ADMINISTRATION
  • the compounds of the present disclosure (also referred to herein as the active ingredients), can be administered by any route appropriate to the condition to be treated.
  • Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intratumoral, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient.
  • An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be dosed orally.
  • a compound of the present disclosure may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer.
  • the compound is administered on a daily or intermittent schedule for the duration of the individual’s life.
  • the dosage or dosing frequency of a compound of the present disclosure may be adjusted over the course of the treatment, based on the judgment of the administering physician.
  • the compound may be administered to an individual (e.g., a human) in an effective amount. In some embodiments, the compound is administered once daily.
  • the compound can be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration.
  • Therapeutically effective amounts of the compound may include from about 0. 00001 mg/kg body weight per day to about 10 mg/kg body weight per day, such as from about 0. 0001 mg/kg body weight per day to about 10 mg/kg body weight per day, or such as from about 0.
  • a compound of the present disclosure may be combined with one or more additional therapeutic agents in any dosage amount of the compound of the present disclosure (e.g., from 1 mg to 1000 mg of compound).
  • Therapeutically effective amounts may include from about 1 mg per dose to about 1000 mg per dose, such as from about 50 mg per dose to about 500 mg per dose, or such as from about 100 mg per dose to about 400 mg per dose, or such as from about 150 mg per dose to about 350 mg per dose, or such as from about 200 mg per dose to about 300 mg per dose.
  • Other therapeutically effective amounts of the compound of the present disclosure are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or about 500 mg per dose.
  • a single dose can be administered hourly, daily, or weekly. For example, a single dose can be administered once every 1 hour, 2, 3, 4, 6, 8, 12, 16 or once every 24 hours. A single dose can also be administered once every 1 day, 2, 3, 4, 5, 6, or once every 7 days. A single dose can also be administered once every 1 week, 2, 3, or once every 4 weeks. In some embodiments, a single dose can be administered once every week. A single dose can also be administered once every month.
  • Kits that comprise a compound of the present disclosure, or a stereoisomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing any of the above, are also included in the present disclosure.
  • a kit further includes instructions for use.
  • a kit includes a compound of the disclosure, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and a label and/or instructions for use of the compounds in the treatment of the indications, such as the diseases or conditions, described herein.
  • kits comprising a compound of the present disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, in combination with one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents are provided.
  • articles of manufacture that include a compound of the present disclosure or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof in a suitable container.
  • the container may be a vial, jar, ampoule, preloaded syringe, and intravenous bag.
  • a compound of the present disclosure can be combined with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.
  • one or more e.g., one, two, three, four, one or two, one to three, or one to four
  • the additional therapeutic agent comprises an apoptotic signal-regulating kinase (ASK-1) inhibitor, a farnesoid X receptor (FXR) agonist, a peroxisome proliferator-activated receptor alpha (PPAR ⁇ ) agonist, fish oil, an acetyl-coA carboxylase (ACC) inhibitor, a TGF ⁇ antagonist, a LPAR antagonist, a SGLT2 inhibitor, a Tpl2 inhibitor, a VAP1 inhibitor or a GLP-1 agonist combination thereof.
  • ASK-1 apoptotic signal-regulating kinase
  • FXR farnesoid X receptor
  • PPAR ⁇ peroxisome proliferator-activated receptor alpha
  • ACC acetyl-coA carboxylase
  • the therapeutic agent, or combination of therapeutic agents are a(n) ACE inhibitor, 2-Acylglycerol O-acyltransferase 2 (DGAT2) inhibitor, Acetaldehyde dehydrogenase inhibitor, Acetyl CoA carboxylase inhibitor, Adrenergic receptor agonist, Alstrom syndrome protein 1(ALMS1)/PKC alpha protein interaction inhibitor, Apelin receptor agonist, Diacylglycerol O acyltransferase 2 inhibitor, Adenosine A3 receptor agonist, Adenosine A3 receptor antagonist, Adiponectin receptor agonist, Aldehyde dehydrogenase 2 stimulator, AKT protein kinase inhibitor, AMP-activated protein kinases (AMPK),
  • AMPK AMP-activated protein kinases
  • Non-limiting examples of the one or more additional therapeutic agents include: ACE inhibitors, such as enalapril; Acetaldehyde dehydrogenase inhibitors, such as ADX-629; Acetyl CoA carboxylase (ACC) inhibitors, such as NDI-010976 (firsocostat), DRM-01, gemcabene, GS-834356, PF-05175157, QLT-091382, PF-05221304; Acetyl CoA carboxylase/Diacylglycerol O acyltransferase 2 inhibitors, such as PF-07055341; Adenosine receptor agonists, such as namodenoson (CF-102), piclidenoson (CF-101), CF-502, CGS21680; Adenosine A3 receptor antagonist, such as FM-101; Adiponectin receptor agonists, such as ADP-355, ADP-399, ALY668-SR; Adrenergic receptor antagonist, such as
  • the one or more additional therapeutic agents are selected from A-4250, AC-3174, acetylsalicylic acid, AK-20, alipogene tiparvovec, AMX-342, AN-3015, anti-TAGE antibody, aramchol, ARI-3037MO, ASP-8232, AXA-1125, bertilimumab, Betaine anhydrous, BI-1467335, BMS-986036, BMS-986171, BMT-053011, BOT-191, BTT- 1023, budesonide, BX-003, CAT-2003, cenicriviroc, CBW-511, CER-209, CF-102, CGS21680, CNX-014, CNX-023, CNX-024, CNX-025, cobiprostone, colesevelam, dabigatran etexilate mesylate, dapagliflozin, DCR-LIV1, deuterated pioglitazone R
  • examples of Acetyl CoA carboxylase (ACC) inhibitors include, but are not limited to, those described in US2013123231, US2019134041, US2017267690, US2018298025.
  • Examples of Acetyl CoA carboxylase (ACC) inhibitors/Farnesoid X receptor (FXR) agonists include, but are not limited to, those described in US2018280394.
  • Examples of Acetyl CoA carboxylase (ACC) inhibitors/Farnesoid X receptor (FXR) agonists/MEKK-5 protein kinase (ASK-1) inhibitors include, but are not limited to, those described in US2018021341, US2018333401.
  • Acetyl CoA carboxylase (ACC)/ MEKK-5 protein kinase (ASK-1) inhibitors include, but are not limited to, those described in US2018311244.
  • Examples of Farnesoid X receptor (FXR) agonists include, but are not limited to, those described in US2014221659, US2020281911, WO 2 020185685.
  • Examples of Farnesoid X receptor (FXR) agonists/MEKK-5 protein kinase (ASK-1) inhibitors include,but are not limited to those described in US2017273952 US201813320.
  • MEKK-5 protein kinase (ASK-1) inhibitors include, but are not limited to, those described in US2011009410, US2013197037, US2016244430, US2016280683.
  • CKD/DKD Patients being treated for cardio-renal diseases such as chronic kidney disease may benefit from combination drug treatment.
  • a compound of the present disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof can be combined with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.
  • the additional therapeutic agent comprises angiotensin converting enzyme (ACE) inhibitors such as enalapril, captopril, ramipril, lisinopril, and quinapril; or angiotensin II receptor blockers (ARBs) such as losartan, olmesartan, and irbesartan; or antihypertensive agents such as amlodipine, nifedipine, and felodipine; SGLT2 inhibitors such as canagliflozin, dapagliflozin, empagliflozing and luseogliflozin, mineralcorticoid receptor antagonists such as finerone, NRF2 activators such as bardoxolone methyl, LPAR antagonists, and apoptotic signal-regulating kinase (ASK-1) inhibitors such as selonsertib.
  • ACE angiotensin converting enzyme
  • ARBs angiotensin II receptor blockers
  • the benefit of combination may be increased efficacy and/or reduced side effects for a component as the dose of that component may be adjusted down to reduce its side effects while benefiting from its efficacy augmented by the efficacy of the compound of Formulas (I-VI) and/or other active component(s).
  • Patients presenting with chronic kidney disease treatable with KHK inhibitors such as a compound of Formula (I-VI) may also exhibit conditions that benefit from co-administration (as directed by a qualified caregiver) of a therapeutic agent or agents that are antibiotic, analgesic, antidepressant and/or anti-anxiety agents in combination with compound of Formula (I-VI).
  • Combination treatments may be administered simultaneously or one after the other within intervals as directed by a qualified caregiver or via a fixed dose (all active ingredients are combined into a single dosage form e.g. tablet) combination of two or more active agents.
  • the therapeutic agent, or combination of therapeutic agents are ACE inhibitors, Adenosine A3 receptor antagonists, Adropin stimulators, Albumin modulators, Aldosterone antagonists, AMP activated protein kinase stimulators, Angiotensin II AT-2 receptor agonists, Angiotensin II receptor antagonists, Angiotensinogen ligand inhibitors, APOA1 gene stimulators, Apolipoprotein L1 modulators, Bone morphogenetic protein-7 ligand modulators, Bromodomain containing protein 2 inhibitors, Bromodomain containing protein 4 inhibitors, Calcium channel inhibitors, Cannabinoid CB1 receptor antagonists, CB1 inverse agonists, CCR2 chemokine antagonists, Chymase inhibitors, Complement C1
  • Non-limiting examples of the one or more additional therapeutic agents include: ACE inhibitors, such as, benazepril, imidapril; Adenosine A3 receptor antagonists, such as FM-101; Adropin stimulators, such as RBT-2; Albumin modulators, such as SYNT-002; Aldosterone/Mineralocorticoid receptor antagonists, such as MT-3995; Allogeneic bone marrow-derived mesenchymal stromal cell therapy, such as ORBCEL-MTM; Allogenic expanded adipose-derived stem cell therapy, such as ElixcyteTM; AMP activated protein kinase stimulator/Proprotein convertase PC9 inhibitors, such as O-304; AMP activated protein kinase stimulators, such as DZCY-01, MK-8722, , PXL-770; Angiotensin II AT-1 receptor/CCR2 chemokine antagonists, such as DMX-200; Angioten
  • the one or more additional therapeutic agents are selected from A-717, ACF-TEI, alanyl-glutamine, ALLN-346, anti-SCF248 antibody, anti- TAGE monoclonal antibodies, anti-TGF beta antibodies, AST-120, BAY-2327949, BI-685509, DP-001, DZ-4001, GDT-01, LNP-1892, MEDI-8367, microRNA-targeting antisense oligonucleotide therapy, MK-2060, MPC-300-IV, NAV-003, Neo-Kidney AugmentTM (NKA), NP-135, NP-160, NP-251, NRF-803, PBI-4610, PHN-033, R-HSC-010, salvianolic acid, SGF-3, SPD-01, SZ-005, TCF-12, UMC119-06, VAR-400, veverimer, VS-105, or XRx-221.
  • IBD inflammatory bowel disease
  • IBD inflammatory bowel disease
  • Other forms of IBD that can be treated with the presently disclosed compounds, compositions and methods include diversion colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), atypical colitis, pseudomembranous colitis, fulminant colitis, autistic enterocolitis, indeterminate colitis, Behçet's disease, gastroduodenal CD, jejunoileitis, ileitis, ileocolitis, Crohn’s (granulomatous) colitis, irritable bowel syndrome, mucositis, radiation induced enteritis, short bowel syndrome, celiac disease, stomach ulcers, diverticulitis, pouchitis, proctitis, chronic diarrhea, or endotoxemia due to
  • the presently disclosed treatment methods can also be applied at any point in the course of the disease.
  • the methods are applied to a subject having IBD during a time period of remission (i.e., inactive disease).
  • the present methods provide benefit by extending the time period of remission (e.g., extending the period of inactive disease) or by preventing, reducing, or delaying the onset of active disease.
  • methods may be applied to a subject having IBD during a period of active disease. Such methods provide benefit by reducing the duration of the period of active disease, reducing or ameliorating one or more symptoms of IBD, or treating IBD.
  • a compound of the present disclosure can be combined with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.
  • agents for treatment of an inflammatory disease or condition include alpha-fetoprotein modulators, adenosine A3 receptor antagonist, adrenomedullin ligands, AKT1 gene inhibitors, antibiotics; antifungals, ASK1 inhibitors, ATPase inhibitors, beta adrenoceptor antagonists, BTK inhibitors, calcineurin inhibitors, carbohydrate metabolism modulators, cathepsin S inhibitors, CCR9 chemokine antagonists, CD233 modulators, CD29 modulators, CD3 antagonists, CD40 ligand inhibitors, CD40 ligand receptor antagonists, chemokine CXC ligand inhibitors, CHST15 gene inhibitors, collagen modulators, COT protein kinase inhibitors, CSF-1 agonist, CSF-1 antagonists, CX3CR1 chemokine modulators, DYRK-1 alpha protein kinase inhibitor, eotaxin ligand inhibitors, EP
  • Anti-inflammatory agents include but are not limited to NSAIDs, non-specific and COX-2 specific cyclooxygenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptors antagonists, immunosuppressants and methotrexate.
  • NSAIDs include, but are not limited to ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, sodium nabumetone, sulfasalazine, tolmetin sodium, and hydroxychloroquine.
  • NSAIDs also include COX-2 specific inhibitors (i.e., a compound that inhibits COX-2 with an IC 50 that is at least 50-fold lower than the IC 50 for COX-1) such as celecoxib, valdecoxib, lumiracoxib, etoricoxib and/or rofecoxib.
  • the anti-inflammatory agent is a salicylate.
  • Salicylates include but are not limited to acetylsalicylic acid or aspirin, sodium salicylate, and choline and magnesium salicylates.
  • the anti-inflammatory agent may also be a corticosteroid.
  • the corticosteroid may be chosen from cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, and prednisone.
  • the anti-inflammatory compound is an anti-C5 monoclonal antibody (such as eculizumab or pexelizumab), a TNF antagonist, such as etanercept, or infliximab, which is an anti-TNF alpha monoclonal antibody. Included herein are methods of treatment in which a compound described herein, is administered in combination with an immunosuppressant.
  • the immunosuppressant is methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, mycophenolate sodium, mercaptopurine, or mycophenolate mofetil.
  • compounds of Formulas (I-VI) or pharmaceutically acceptable salt or stereoisomer thereof are useful in a method of treating and/or preventing a KHK (ketohexokinase) mediated disease or condition.
  • a method for treating and/or preventing a KHK mediated disease or condition includes administering to a subject in need thereof a pharmaceutically effective amount of a compound of the present disclosure or pharmaceutically acceptable salt or stereoisomer thereof.
  • the disease or condition comprises chronic kidney disease (CKD), diabetic kidney disease (DKD), kidney disease, kidney fibrosis, kidney insufficiency, acute kidney injury, tubular disfunction, lupus nephritis, 2,8-dihydroxyadenine nephropathy, renal transplant rejection, renal protection against drugs inducing Fanconi’s syndrome, hereditary fructose intolerance, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), non-alcoholic fatty liver disease (NAFLD), liver disease, liver fibrosis, metabolic syndrome, obesity, hyperlipidemia, hypertriglyceridemia, hypertension, fibrosis, steatosis, cirrhosis, cardiometabolic syndrome, insulin resistance, cardiovascular disease, heart failure, type 1 and type 2 diabetes mellitus, irritable bowel syndrome disease (IBD), ulcerative colitis, Crohn's disease, hyperuricemia, gout, arthritis, osteopo
  • a method of treating and/or preventing a non-alcoholic fatty liver disease comprises administering to a subject in need thereof a compound of the present disclosure or a pharmaceutically acceptable salt or stereoisomer thereof.
  • a method of treating and/or preventing chronic kidney disease comprises administering to a subject in need thereof a compound of the present disclosure or a pharmaceutically acceptable salt or stereoisomer thereof.
  • a method of treating and/or preventing irritable bowel syndrome disease (IBD) comprises administering to a subject in need thereof a compound of the present disclosure or a pharmaceutically acceptable salt or stereoisomer thereof.
  • a pharmaceutical composition for use in treating a KHK mediated disease or condition described herein comprising a compound of the present disclosure or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the present disclosure also describes a use for the manufacture of a medicament in treating a KHK mediated disease or condition comprising a compound of the present disclosure or a pharmaceutically acceptable salt or stereoisomer thereof.
  • Medicaments as referred to herein may be prepared by conventional processes, including the combination of a compound according to the present disclosure and a pharmaceutically acceptable carrier.
  • a compound of the present disclosure or a pharmaceutically acceptable salt or stereoisomer thereof for the treatment of a KHK mediated disease or condition.
  • a compound of the present disclosure or a pharmaceutically acceptable salt or stereoisomer thereof for the prevention of a KHK mediated disease or condition.
  • Many general references providing commonly known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds are available (see, e.g., Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7 th edition, Wiley-Interscience, 2013).
  • Compounds as described herein can be purified by any of the means known in the art, including chromatographic means, such as high-performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins.
  • the disclosed compounds can be purified via silica gel and/or alumina chromatography. See, e.g., Introduction to Modern Liquid Chromatography, 2nd ed. , ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, E. Stahl (ed. ), Springer-Verlag, New York, 1969.
  • the present disclosure generally provides a specific enantiomer or diastereomer as the desired product, although the stereochemistry of the enantiomer or diastereomer was not determined in all cases.
  • the stereochemistry of the specific stereocenter in the enantiomer or diastereomer is not determined, the compound is drawn without showing any stereochemistry at that specific stereocenter even though the compound can be substantially enantiomerically or disatereomerically pure.
  • Representative syntheses of compounds of the present disclosure are described in schemes below, and the examples that follow. The compounds detailed in the Examples were synthesized according to the general synthetic methods described below. Compounds were named using ChemDraw version 18. 1. 0.
  • (2S,3R)-1-(4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-yl benzoate The title compound was prepared in a method analogous to2-[(2S)-2-methylazetidin-1-yl]-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-ol using (2S,3R)-2-methylazetidin-3-yl benzoate instead of (2S)-2-methylazetidine hydrochloride.
  • Solvents were generally selected from, but not limited to 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, toluene, xylene, benzene, chlorobenzene, acetonitrile, N,N- dimethylformamide, N- methylpyrrolidone, dimethylsulfoxide, methanol, ethanol, 2-propanol or water.
  • Palladium catalysts were generally selected from, but not limited to, Pd(PPh 3 ) 4 , Pd(dppf)Cl2, Pd(OAc)2, PdCl2 Pd XPhos G1, G2, G3, or G4 precatalysts, Pd SPhos G1, G2, G3, or G4 precatalysts, or Pd 2 dba 3 with or without phosphine ligands, selected from, but not limited to, SPhos, XPhos, RuPhos, XantPhos, PCy 3 , PPh 3 , or dppf.
  • Bases were generally selected from, but not limited to, sodium carbonate, potassium carbonate, cesium carbonate, tribasic potassium phosphate, sodium hydroxide, potassium hydroxide, sodium acetate, potassium acetate, cesium fluoride, triethyl amine, diisopropylethyl amine, or pyridine. Isomers that were separated by chiral chromatography were arbitrarily assigned stereochemistry.
  • N(iPr)2Et (0.13 mL, 98 mg, 0.76 mmol, 4.0 equiv.) was added and the mixture was heated to 90 o C for 18 hours. The mixture was concentrated and subject to HPLC (0.1% TFA in MeCN-0.1% TFA in H 2 O) to give the title compound (36 mg, 0.14 mol).
  • 1,4-Dioxane (1 mL) was added and the mixture was sparged with nitrogen for 5 minutes before being heated to 130 o C for 1 hour in a CEM microwave reactor.
  • the mixture was cooled to ambient temperature and filtered, washing with 1,4-dioxane (0.5 mL).
  • a microwave reaction tube was charged with the filtrate and 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine (21.3 mg, 0.095 mmol).
  • Aqueous Na 2 CO 3 (2 M, 0.2 mL) was added and the reaction mixture was sparged with nitrogen for 5 minutes before being heated to 130 o C for 1 hour in a CEM microwave reactor.
  • the mixture was heated to 110 o C for 18 h, cooled to ambient temperature and poured over ice.
  • the aqueous mixture was extracted twice with DCM.
  • the combined organic layers were dried over MgSO 4 , filtered and concentrated. The crude was used without further purification.
  • 1,4-Dioxane (2.0 mL) was added, and the mixture was sparged with nitrogen for 2 min. The mixture was heated to 120 o C for 18 hrs, cooled to ambient temperature, and filtered over Celite®, washing with DCM. The mixture was concentrated and the residue subjected to HPLC (0.1% TFA in MeCN-0.1% TFA in H 2 O) to give the title compound.
  • the vial was purged with nitrogen, and Pd/C (5% weight, 41 mg, 0.019, 10 mol%) was added. A balloon of H 2 gas was sparged through the solution with stirring for 2 hours. The mixture was filtered over Celite®, concentrated, and subject to reverse phase HPLC (0.1% TFA in MeCN-0.1% TFA in H 2 O) to give the title compound.
  • the starting material was dissolved in DCM (0.3 M), and mCBPA (1.5 equiv.) was added. The mixture was allowed to stir for 30 min. K 2 CO 3 (2M aq) was added and the mixture was extracted with DCM. The combined organics were dried over Na2SO4, filtered, and concentrated. The residue was subject to flash column chromatography (hexanes – ethyl acetate) to give the desired product.
  • the reaction mixture was purged with argon five times and heated under argon to 110 o C for 1 hour. After that the mixture was cooled down to room temperature and was diluted with DMSO (1mL) and water (0.2 mL), and was acidified with trifluoroacetic acid (16 ⁇ L, 0.21 mmol). The solids were filtered off and the solution was purified by preparative reverse phase HPLC (0.1% TFA in MeCN-0.1% TFA in H 2 O) to give the title compound.
  • Example 2 methyl (S)-3-(2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)propanoate
  • the title compound was prepared in a method analogous to General Method A using methyl 3- [2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate instead of 3-pyridylboronic acid followed by General Method B.
  • Example 3 methyl (S)-2-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)acetate
  • the title compound was prepared in a method analogous to General Method A using methyl 2- [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate instead of 3-pyridylboronic acid followed by General Method B.
  • Example 5 (S)-3-(2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)phenyl)propanoic acid
  • the title compound was prepared in a method analogous to General Method C using methyl (S)- 3-(2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)propanoate instead of (S)-3-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)phenyl)propanoate.
  • Example 6 (S)-2-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)phenyl)acetic acid
  • the title compound was prepared in a method analogous to General Method C using methyl (S)- 2-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)acetate instead of (S)-3-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)phenyl)propanoate.
  • Example 7 (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzonitrile
  • the title compound was prepared in a method analogous to General Method A using (3- cyanophenyl)boronic acid instead of 3-pyridylboronic acid followed by General Method B.
  • Example 8 (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzamide
  • Example 9 (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzoic acid
  • the title compounds were prepared according to General Method J.
  • Example 10 (S)-2-(2-methylazetidin-1-yl)-4-phenyl-5,8-dihydro-6H-pyrano[3,4- d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A using phenylboronic acid and 2,4-dichloro-5,8-dihydro-6H-pyrano[3,4-d]pyrimidine instead of 3- pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by General Method B.
  • Example 11 (S)-1-methyl-5-(2-methylazetidin-1-yl)-7-phenyl-1H-pyrazolo[4,3- d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A using phenylboronic acid and 5,7-dichloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine instead of 3- pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by General Method B.
  • Example 12 (S)-2-(2-methylazetidin-1-yl)-4-phenylfuro[3,2-d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A using phenylboronic acid and 2,4-dichlorofuro[3,2-d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by General Method B.
  • Example 13 (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)isothiazole
  • the title compound was prepared in a method analogous to General Method A using 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazole instead of 3-pyridylboronic acid followed by General Method B.
  • Example 14 (S)-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)isothiazole
  • the title compound was prepared in a method analogous to General Method A using 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazole instead of 3-pyridylboronic acid followed by General Method B.
  • Example 15 (S)-2-(2-methylazetidin-1-yl)-4-(pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared according to General Method A followed by General Method B.
  • Example 16 (S)-2-(2-methylazetidin-1-yl)-4-(pyrimidin-5-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A using pyrimidin- 5-ylboronic acid instead of 3-pyridylboronic acid followed by General Method B.
  • Example 17 (S)-4-(1-methyl-1H-pyrazol-3-yl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A using 1-methyl- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole instead of 3-pyridylboronic acid followed by General Method B.
  • Example 18 (S)-2-(2-methylazetidin-1-yl)-4-(1H-pyrazol-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A using tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate instead of 3- pyridylboronic acid followed by General Method B.
  • the tert-butyl carboxylate was cleaved under the reaction conditions.
  • Example 19 (S)-2-(2-methylazetidin-1-yl)-4-(1H-pyrazol-4-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A using tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate instead of 3- pyridylboronic acid followed by General Method B.
  • the tert-butyl carboxylate was cleaved under the reaction conditions.
  • Example 20 (S)-4-(1-methyl-1H-pyrazol-5-yl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A using 1-methyl- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole instead of 3-pyridylboronic acid followed by General Method B.
  • Example 21 (S)-2-(2-methylazetidin-1-yl)-4-(pyridin-2-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine A vial was charged with 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (40 mg, 0.21 mmol, 1.0 equiv.), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (60.7 mg, 0.30 mmoL, 1.4 equiv), Pd(dppf)Cl2-DCM complex (8.8 mg, 0.011 mmol, 5 mol%), CuCl (20.9 mg, 0.21 mmol, 1 equiv.), Cs 2 CO 3 (138 mg, 0.42 mmol, 2.0 equiv.), and DMF (2 mL).
  • Example 22 (S)-2-(2-methylazetidin-1-yl)-4-(pyridin-4-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine A vial was charged with 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (40 mg, 0.21 mmol, 1.0 equiv.), 4-pyridylboronic acid (60.7 mg, 0.30 mmoL, 1.4 equiv), Pd(dppf)Cl 2 -DCM complex (8.8 mg, 0.011 mmol, 5 mol%), CuCl (20.9 mg, 0.21 mmol, 1 equiv.), Cs 2 CO 3 (138 mg, 0.42 mmol, 2.0 equiv.), and DMF (2 mL).
  • Example 23 (S)-4-(1-methyl-1H-pyrazol-4-yl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A using 1-methyl- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole instead of 3-pyridylboronic acid followed by General Method B.
  • Example 24 (S)-3-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-1H-pyrazol-1-yl)propanoic acid
  • (S)-2-(2-methylazetidin-1-yl)-4-(1H-pyrazol-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine (12 mg, 0.033 mmol, 1 equiv.)
  • K 2 CO 3 (9.0 mg, 0.065 mmol, 2 equiv.
  • MeCN 0.5 mL
  • methyl prop-2-enoate 84 mg, 0.975 mmol, 30 equiv.
  • the sealed vial was heated to 120 o C for 2 hours, and was then cooled to ambient temperature and concentrated. The resulting residue was dissolved in MeOH (0.5 mL) and NaOH (2M aq., 0.5 mL) was added. The mixture was heated to 60 o C for 20 min. The mixture was cooled to ambient temperature, concentrated, and subjected to HPLC (0.1% TFA in MeCN-0.1% TFA in H 2 O) to give the title compound.
  • Example 25 (S)-3-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-1H-pyrazol-1-yl)propanoic acid
  • a vial was charged with 2-[(2S)-2-methylazetidin-1-yl]-4-(1H-pyrazol-4-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine (6 mg, 0.016 mmol, 1 equiv.), K2CO3 (4.5 mg, 0.033 mmol, 2 equiv.) and MeCN (0.5 mL), followed by methyl prop-2-enoate (42 mg, 0.49 mmol, 30 equiv.).
  • the sealed vial was heated to 120 o C for 15 min, and was then cooled to ambient temperature and concentrated. The resulting residue was dissolved in MeOH (0.5 mL) and NaOH (2M aq., 0.5 mL) was added. The mixture was heated to 60 o C for 20 min. The mixture was cooled to ambient temperature, concentrated, and subjected to HPLC (0.1% TFA in MeCN-0.1% TFA in H 2 O) to give the title compound.
  • Example 26 (S)-5-(2-methylazetidin-1-yl)-7-phenylthiazolo[5,4-d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A using phenylboronic acid and 5,7-dichlorothiazolo[5,4-d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by General Method B.
  • Example 27 (S)-2-methyl-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method A using 2-methyl- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide instead of 3-pyridylboronic acid followed by General Method B.
  • Example 28 (S)-N-methyl-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method A using [3- (methylcarbamoyl)phenyl]boronic acid instead of 3-pyridylboronic acid followed by General Method B.
  • Example 29 (S)-3-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)phenyl)propenamide
  • a vial was charged with methyl 3-[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]propanoate (35 mg, 0.10 mmol, 1.0 equiv.), EtOH (1 mL), and NH4OH (25% aq., 2mL) and heated to 100 o C for 18 hr.
  • Example 30 6-cyclopropyl-2-((S)-2-methylazetidin-1-yl)-4-phenyl-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method H using methyl 4- cyclopropyl-2-oxocyclopentane-1-carboxylate instead of 2-oxobicyclo[3.1.0]hexane-3- carboxylate and phenyl boronic acid instead of (3-carbamoylphenyl)boronic acid.
  • Example 31 2-((S)-2-methylazetidin-1-yl)-4-phenyl-5,6,7,8-tetrahydro-5,8- methanoquinazoline
  • the title compound was prepared in a method analogous to General Method H using methyl 3- oxobicyclo[2.2.1]heptane-2-carboxylate instead of 2-oxobicyclo[3.1.0]hexane-3-carboxylate and phenyl boronic acid instead of (3-carbamoylphenyl)boronic acid.
  • Example 32 3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method A using (3- carbamoylphenyl)boronic acid instead of 3-pyridylboronic acid followed by General Method B using (2S,3R)-2-methylazetidin-3-ol hydrochloride salt instead of (2S)-2-methylazetidine (R)- camphorsulfonic acid salt.
  • Example 33 3-(2-((S)-2-methylazetidin-1-yl)-5,6,7,8-tetrahydro-5,8-methanoquinazolin-4- yl)benzamide
  • the title compound was prepared in a method analogous to General Method H using methyl 3- oxobicyclo[2.2.1]heptane-2-carboxylate instead of 2-oxobicyclo[3.1.0]hexane-3-carboxylate.
  • Example 34 (S)-2-methyl-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)thiazole
  • the title compound was prepared in a method analogous to General Method A using 2-methyl- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole instead of 3-pyridylboronic acid followed by General Method B.
  • Example 35 (S)-1-methyl-5-(2-methylazetidin-1-yl)-7-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3- d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A using 5,7- dichloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazole-1-carboxylate instead of 3-pyridylboronic acid and 2,4-dichloro-6,7- dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by General Method B.
  • Example 36 (S)-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)thiazole
  • the title compound was prepared in a method analogous to General Method E using tributyl(thiazol-4-yl)stannane instead of ethyl 2-tributylstannylimidazo[5,1-b]thiazole-7- carboxylate.
  • Example 37 (S)-3-(1-methyl-5-(2-methylazetidin-1-yl)-1H-pyrazolo[4,3-d]pyrimidin-7- yl)benzenesulfonamide
  • the title compound was prepared in a method analogous to General Method A using 5,7- dichloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine and 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzenesulfonamide instead of 3-pyridylboronic acid and 2,4-dichloro-6,7- dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by General Method B.
  • Example 38 3-(5-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-1-methyl-1H-pyrazolo[4,3- d]pyrimidin-7-yl)benzenesulfonamide
  • the title compound was prepared in a method analogous to General Method A using 5,7- dichloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine and 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzenesulfonamide instead of 3-pyridylboronic acid and 2,4-dichloro-6,7- dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by General Method B using (2S,3R)-2-methylazetidin-3-ol hydrochloride salt instead of (2S)-2-methylazetidine.
  • Example 39 (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-1H-indazole
  • the title compound was prepared in a method analogous to General Method A using 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole instead of 3-pyridylboronic acid followed by General Method B.
  • Example 40 (S)-N-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)phenyl)acetamide
  • the title compound was prepared in a method analogous to General Method A using (3- acetamidophenyl)boronic acid instead of 3-pyridylboronic acid followed by General Method B.
  • Example 41 N-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)acetamide
  • the title compound was prepared in a method analogous to General Method A using (3- acetamidophenyl)boronic acid instead of 3-pyridylboronic acid followed by General Method B using (2S,3R)-2-methylazetidin-3-ol hydrochloride salt instead of (2S)-2-methylazetidine (R)- camphorsulfonic acid salt.
  • Example 42 (S)-N-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)phenyl)methanesulfonamide
  • the title compound was prepared in a method analogous to General Method A using [3- (methanesulfonamido)phenyl]boronic acid instead of 3-pyridylboronic acid followed by General Method B.
  • Example 43 N-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)methanesulfonamide
  • the title compound was prepared in a method analogous to General Method A using [3- (methanesulfonamido)phenyl]boronic acid instead of 3-pyridylboronic acid followed by General Method B using (2S,3R)-2-methylazetidin-3-ol hydrochloride salt instead of (2S)-2- methylazetidine (R)-camphorsulfonic acid salt.
  • Example 44 (S)-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-1H-indazole
  • the title compound was prepared in a method analogous to General Method A using 6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole instead of 3-pyridylboronic acid followed by General Method B.
  • Example 45 (S)-2-(2-methylazetidin-1-yl)-4-(thiophen-2-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method E using 5- tributylstannylthiophene-2-carbonitrile instead of ethyl 2-tributylstannylimidazo[5,1-b]thiazole- 7-carboxylate followed by General Method B using 2-chloro-4-(2-thienyl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine instead of 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine.
  • Example 46 2-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)phenyl)cyclopropane-1-carboxylic acid
  • ethyl (trans)-2-(3-bromophenyl)cyclopropanecarboxylate 200 mg, 0.74 mmol, 1.0 equiv.
  • Pd(dppf)Cl2-DCM complex 59 mg, 0.074 mmol, 10 mol%)
  • B2pin2 (283 mg, 1.11 mmol, 1.5 equiv.
  • KOAc 219 mg, 2.23 mmol, 3.0 equiv.
  • the vial was purged with nitrogen, and 1,4-dioxane (3.0 mL) was added.
  • the mixture was heated to 100 o C for 1 hour, cooled to ambient temperature, and subjected to flash column chromatography (0- 100% hexane/ ethyl acetate) to give ethyl 2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]cyclopropanecarboxylate.
  • the title compound was prepared in a method analogous to General Method C using ethyl 2-[3- [2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]phenyl]cyclopropanecarboxylate instead of methyl (S)-3-(3-(2-(2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)propanoate.
  • Example 47 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid
  • the title compound was prepared in a method analogous to General Method A using 2-[3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylate instead of 3- pyridylboronic acid followed by General Method B using (2S,3R)-2-methylazetidin-3-ol hydrochloride salt instead of (2S)-2-methylazetidine.
  • Example 48 2-(3-(2-((2S,3R)-3-fluoro-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid
  • the title compound was prepared in a method analogous to General Method A using 2-[3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylate instead of 3- pyridylboronic acid followed by General Method B using (2S,3R)-3-fluoro-2-methylazetidine hydrochloride salt instead of (2S)-2-methylazetidine (R)-camphorsulfonic acid salt.
  • Example 49 (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)thiophene-2-carbonitrile
  • the title compound was prepared in a method analogous to General Method E using 5- tributylstannylthiophene-2-carbonitrile instead of ethyl 2-tributylstannylimidazo[5,1-b]thiazole- 7-carboxylate.
  • Example 51 tert-butyl (S)-(2-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamido)ethyl)carbamate
  • the title compound was prepared in a method analogous to General Method G using (S)-3-(2- (2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and tert-butyl (2-aminoethyl)carbamate instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively.
  • Example 52 (S)-N-(2-aminoethyl)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method I using tert-butyl (S)-(2-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzamido)ethyl)carbamate instead of (S)-4-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)piperazine-1-carboxylate
  • Example 53 (S)-N-(2-(methylamino)ethyl)-3-(2-(2-methylazetidin-1
  • Example 54 (S)-N-(2-hydroxyethyl)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide
  • the title compound was prepared in a method analogous to General Method F using 3-bromo-N- (2-hydroxyethyl)benzenesulfonamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 55 (S)-2-(2-methylazetidin-1-yl)-4-(6-phenylpyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 2-phenyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine instead of 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 56 (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)thiophene-2-carboxamide
  • the title compounds were prepared according to General Method J using (S)-5-(2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carbonitrile instead of (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzonitrile.
  • Example 57 5-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamide
  • the title compound was prepared in a method analogous to General Method E using 5- tributylstannylthiophene-2-carbonitrile and 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine instead of ethyl 2-tributylstannylimidazo[5,1-b]thiazole-7-carboxylate and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by General Method B, using (2S,3R)-2-methylazetidin-3-ol instead of (2S)-2-methylazetidine and General
  • Example 58 5-(2-((2S,3R)-3-fluoro-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamide
  • the title compound was prepared in a method analogous to General Method E using 5- tributylstannylthiophene-2-carbonitrile and 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine instead of ethyl 2-tributylstannylimidazo[5,1-b]thiazole-7-carboxylate and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by General Method B, using (2S,3R)-3-fluoro-2-methylazetidine instead of (2S)-2-methylazetidine
  • Example 59 N-((1S*,2S*)-2-hydroxycyclobutyl)-3-(2-((S)-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method G using (S)-3-(2- (2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and rac- (1S*,2S*)-2-aminocyclobutanol instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)- 6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively.
  • Example 60 N-((1S*,2R*)-2-hydroxycyclobutyl)-3-(2-((S)-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method G using (S)-3-(2- (2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and rac- (1S*,2R*)-2-aminocyclobutanol instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)- 6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively.
  • Example 61 (S)-N-(2-hydroxyethyl)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method G using (S)-3-(2- (2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and ethanolamine instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively.
  • Example 62 3-((5R,8S)-2-((S)-2-methylazetidin-1-yl)-5,6,7,8-tetrahydro-5,8- methanoquinazolin-4-yl)benzamide
  • Example 63 3-((5S,8R)-2-((S)-2-methylazetidin-1-yl)-5,6,7,8-tetrahydro-5,8- methanoquinazolin-4-yl)benzamide Isomers were separated by SFC (25% MeOH in CO 2 , CHIRALPAK IG, 100 x 4.6 mm, 3 mL/min).(see Example 33)
  • Example 64 (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-N-(1H-pyrazol-4-yl)benzamide The title compound was prepared in a method analogous to General Method G
  • Example 65 (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-N-(1H-pyrazol-3-yl)benzamide
  • the title compound was prepared in a method analogous to General Method G using (S)-3-(2- (2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and 1H- pyrazol-3-amine instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively.
  • Example 66 (S)-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzoyl)glycine
  • the title compound was prepared in a method analogous to General Method G using (S)-3-(2- (2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and methyl glycinate instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively, followed by General Method C.
  • Example 67 (S)-1-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzamido)cyclopropane-1-carboxylic acid
  • the title compound was prepared in a method analogous to General Method G using (S)-3-(2- (2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and methyl 1-aminocyclopropane-1-carboxylate hydrochloride salt instead of 2-(3-(2-((2S,3R)-3-hydroxy-2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1- carboxylic acid and ammonia, respectively, followed by General Method C.
  • Example 68 (S)-1-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzoyl)azetidine-3-carboxylic acid
  • the title compound was prepared in a method analogous to General Method G using (S)-3-(2- (2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and methyl azetidine-3-carboxylate hydrochloride salt instead of 2-(3-(2-((2S,3R)-3-hydroxy-2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1- carboxylic acid and ammonia, respectively, followed by General Method C.
  • Example 69 (S)-2-(1-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzoyl)azetidin-3-yl)acetic acid
  • the title compound was prepared in a method analogous to General Method G using (S)-3-(2- (2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and methyl 2-(azetidin-3-yl)acetate trifluoroacetic acid salt instead of 2-(3-(2-((2S,3R)-3-hydroxy-2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1- carboxylic acid and ammonia, respectively, followed by General Method C.
  • Example 70 (S)-2-(5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-1H-indazol-3-yl)acetic acid tert-Butyl (S)-2-(5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H- indazol-3-yl)acetate was prepared in a method analogous to General Method F using tert-butyl 2-(5-bromo-1H-indazol-3-yl)acetate instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 71 (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)aniline
  • the title compound was prepared in a method analogous to General Method A using 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)aniline instead of 3-pyridylboronic acid followed by General Method B.
  • Example 72 (S)-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide
  • the title compound was prepared in a method analogous to General Method F using 6-bromo- 2,3-dihydrobenzo[d]isothiazole 1,1-dioxide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3- one.
  • Example 74 (S)-((3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)phenyl)sulfonyl)glycine
  • the title compound was prepared in a method analogous to General Method K using 3- bromobenzenesulfonyl chloride and methyl glycinate instead of 1-methylimidazole-4-sulfonyl chloride and (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)aniline, respectively, followed by General Method F using methyl ((3- bromophenyl)sulfonyl)glycinate instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one, followed by General Method C.
  • Example 75 (S)-2-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzyl)isothiazolidine 1,1-dioxide
  • the title compound was made in a method analogous to General Method D, using (S)-4-chloro- 2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 2- bromoimidazo[5,1-b]thiazole-7-carboxylate, followed by General Method E, using 2-(3- bromobenzyl)isothiazolidine 1,1-dioxide instead of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidine.
  • Example 76 (S)-3,5-dimethyl-N-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)isoxazole-4-sulfonamide
  • the title compound was prepared in a method analogous to General Method K using 3,5- dimethylisoxazole-4-sulfonyl chloride instead of 1-methylimidazole-4-sulfonyl chloride.
  • Example 77 (S)-1-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzoyl)azetidine-2-carboxylic acid
  • the title compound was prepared in a method analogous to General Method G using (S)-3-(2- (2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and methyl (S)-azetidine-2-carboxylate hydrochloride salt instead of 2-(3-(2-((2S,3R)-3-hydroxy-2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1- carboxylic acid and ammonia, respectively, followed by General Method C.
  • Example 78 (R)-1-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzoyl)azetidine-2-carboxylic acid
  • the title compound was prepared in a method analogous to General Method G using (S)-3-(2- (2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzoic acid and methyl (R)-azetidine-2-carboxylate hydrochloride salt instead of 2-(3-(2-((2S,3R)-3-hydroxy-2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1- carboxylic acid and ammonia, respectively, followed by General Method C.
  • Example 79 (rac)-3-(2-(6-azabicyclo[3.2.0]heptan-6-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide
  • the title compound was prepared in a method analogous to General Method B using 6- azabicyclo[3.2.0]heptane and 3-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzenesulfonamide instead of (2S)-2-methylazetidine 2-chloro-4-(pyridin-3-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidine, respectively.
  • Example 80 (rac)-3-(2-((1S*,5S*,6R*)-6-hydroxy-2-azabicyclo[3.2.0]heptan-2-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide
  • the title compound was prepared in a method analogous to General Method B using (rac)- (1S*,5S*,6R*)-2-azabicyclo[3.2.0]heptan-6-ol hydrochloride salt and 3-(2-chloro-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide instead of (2S)-2-methylazetidine and 2- chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 81 (S)-2-(N-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)sulfamoyl)acetic acid
  • the title compund was prepared in a method analogous to General Method K using ethyl 2- (chlorosulfonyl)acetate instead of 1-methylimidazole-4-sulfonyl chloride, followed by General Method C.
  • Example 82 2-(N-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)sulfamoyl)acetic acid
  • the title compound was prepared in a method analogous to General Method A, using 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)aniline instead of 3-pyridylboronic acid, followed by General Method K using ethyl 2-(chlorosulfonyl)acetate instead of 1-methylimidazole-4- sulfonyl chloride, followed by General Method B using (2S,3R)-2-methylazetidin-3-ol instead of (2S)-2-methylazetidine, followed by General Method C.
  • Example 83 (S)-3-(N-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)sulfamoyl)propanoic acid
  • the title compound was prepared in a method analogous to General Method K using methyl 3- (chlorosulfonyl)propanoate instead of 1-methylimidazole-4-sulfonyl chloride, followed by General Method C.
  • Example 84 (S)-N-(5-(N-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)sulfamoyl)thiazol-2-yl)acetamide
  • the title compound was prepared in a method analogous to General Method K using 2- acetamidothiazole-5-sulfonyl chloride instead of 1-methylimidazole-4-sulfonyl chloride.
  • Example 85 (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)isothiazole-3-carboxamide
  • the title compound was prepared in a method analogous to General Method F using 5- bromoisothiazole-3-carboxamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 87 (S)-8-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-2-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one
  • the title compound was prepared in a method analogous to General Method Q, using tert-butyl (R)-(2-hydroxypropyl)carbamate instead of tert-butyl (S)-(1-hydroxypropan-2-yl)carbamate, followed by General Method F, using (S)-8-bromo-2-methyl-3,4-dihydrobenzo[f][1,4]oxazepin- 5(2H)-one and 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopent
  • Example 88 (S)-2-(2-methylazetidin-1-yl)-4-(3-((methylsulfonyl)methyl)phenyl)-6,7- dihydro-5H-cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method F using 2-[(3- bromophenyl)methylsulfonyl]acetic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one. In situ decarboxylation was the exclusive product.
  • Example 89 (1S,2S)-2-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid
  • Example 90 (1R,2R)-2-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid
  • Isomers were separated by SFC (25% MeOH in CO 2 , CHIRALPAK AD-H, 100 x 4.6 mm, 3 mL/min).
  • Example 91 (S)-N-(2-hydroxyethyl)-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine N-(2-hydroxyethyl)- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide instead of 2,4-dichloro-6,7-dihydro- 5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 92 (R)-3-(2-(2-(hydroxymethyl)azetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide
  • the title compound was prepared in a method analogous to General Method B using (R)- azetidin-2-ylmethanol and 3-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzenesulfonamide instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 93 4-(2-((2S,3R)-3-amino-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method B using tert-butyl ((2S,3R)-2-methylazetidin-3-yl)carbamate hydrochloride salt and 4-(2-chloro-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide instead of (2S)-2-methylazetidine and 2-chloro-4- (pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by General Method I.
  • Example 94 (R)-8-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-2-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one
  • the title compound was prepared in a method analogous to General Method Q, using tert-butyl (S)-(2-hydroxypropyl)carbamate instead of tert-butyl (S)-(1-hydroxypropan-2-yl)carbamate, followed by General Method F, using (R)-8-bromo-2-methyl-3,4-dihydrobenzo[f][1,4]oxazepin- 5(2H)-one and 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopent
  • Example 95 (R)-4-(2-(2-(hydroxymethyl)azetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method B using (R)- azetidin-2-ylmethanol and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 96 2-cyclopropyl-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine
  • the title compound was prepared according to General Method L.
  • Example 97 2-cyclobutyl-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method L using cyclobutylzinc bromide instead of cyclopropylzinc bromide.
  • Example 98 2-(bicyclo[2.2.1]heptan-2-yl)-4-phenyl-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method L using bicyclo[2.2.1]heptan-2-ylzinc bromide instead of cyclopropylzinc bromide.
  • Example 99 2-(azetidin-3-yl)-4-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method L using (1-(tert- butoxycarbonyl)azetidin-3-yl)zinc iodide instead of cyclopropylzinc bromide, followed by General Method I.
  • Example 100 (S)-2-methyl-5-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)-1,3,4-oxadiazole
  • the title compound was prepared in a method analogous to General Method F using 4-(5- methyl-1,3,4-oxadiazol-2-yl)phenyl]boronic acid instead of 6-bromo-1,1-dioxo-1,2- benzothiazol-3-one.
  • Example 101 (S)-4-(4-(1-methyl-1H-imidazol-2-yl)phenyl)-2-(2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method F using [4-(1- methylimidazol-2-yl)phenyl]boronic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 102 (S)-4-(4-(1H-pyrazol-1-yl)phenyl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method F using (4-pyrazol- 1-ylphenyl)boronic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 103 (S)-4-(4-(1H-pyrazol-5-yl)phenyl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method F using [4-(1H- pyrazol-5-yl)phenyl]boronic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 104 (S)-4-(4-(1H-tetrazol-5-yl)phenyl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method F using [4-(1H- tetrazol-5-yl)phenyl]boronic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 105 4-(2-(2,3-dimethylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzamide
  • the title compound was prepared in a method analogous to General Method B 2,3- dimethylazetidine hydrochloride salt and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzamide instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 106 4-(2-((2S,3R)-2,3-dimethylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • Example 107 4-(2-((2S,3S)-2,3-dimethylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • Example 108 4-(2-((2R,3S)-2,3-dimethylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • Example 109 4-(2-((2R,3R)-2,3-dimethylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide Isomers were separated by SFC
  • Example 111 4-(2-(2-ethynylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzamide
  • the title compound was prepared in a method analogous to General Method B using (rac)-2- ethynylazetidine hydrochloride salt and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzamide instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 112 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxamide
  • the title compound was prepared according to General Method G.
  • Example 113 (1S,2S)-2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid
  • Example 114 (1R,2R)-2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid Isomers were separated by SFC (35% MeOH in CO 2 , CHIRALPAK AD-H, 100 x 4.6 mm, 3 mL/min)
  • Example 115 1-(3-(2-(S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]
  • Example 116 (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)isophthalamide
  • the title compound was prepared in a method analogous to General Method F using 5- bromoisophthalamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 117 4-(2-(2-methyl-3-oxocyclopent-1-en-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method A using 2-methyl- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-en-1-one and 4-(2-chloro-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide instead of 3-pyridylboronic acid and 2,4- dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 118 (S)-2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)imidazo[5,1-b]thiazole-7-carboxylic acid
  • the title compound was prepared according to General Method E, followed by General Method C.
  • Example 119 (S)-2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)imidazo[5,1-b]thiazole-7-carboxamide
  • the title compound was prepared in a method analogous to General Method G using (S)-2-(2- (2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)imidazo[5,1-b]thiazole-7- carboxylic acid instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid.
  • Example 120 (S)-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-1H-indazol-3-ol
  • the title compound was prepared in a method analogous to General Method D using 6-bromo- 1H-indazol-3-ol instead of 2-bromoimidazo[5,1-b]thiazole-7-carboxylate, followed by General Method E.
  • Example 121 (S)-2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)imidazo[2,1-b]thiazole
  • the title compound was prepared in a method analogous to General Method D using 2- bromoimidazo[2,1-b]thiazole, followed by General Method E.
  • Example 122 (S)-2-fluoro-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide
  • the title compound was prepared in a method analogous to General Method F using 5-bromo-2- fluoro-benzenesulfonamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 123 (S)-2-methyl-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide
  • the title compound was prepared in a method analogous to General Method F using 5-bromo-2- methyl-benzenesulfonamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 124 (S)-4-(3-(2-methylazetidin-1-yl)-2,4-diazabicyclo[4.2.0]octa-1,3,5-trien-5- yl)benzamide
  • the title compound was prepared in a method analogous to General Method A using 5-chloro-3- (methylsulfonyl)-2,4-diazabicyclo[4.2.0]octa-1,3,5-triene and (4-carbamoylphenyl)boronic acid instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, followed by General Method B.
  • Example 125 4-(3-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-2,4-diazabicyclo[4.2.0]octa- 1,3,5-trien-5-yl)benzamide
  • the title compound was prepared in a method analogous to General Method A using 5-chloro-3- (methylsulfonyl)-2,4-diazabicyclo[4.2.0]octa-1,3,5-triene and (4-carbamoylphenyl)boronic acid instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, followed by General Method B, using (2S,3R)-2-methylazetidin-3-ol instead of (2S)-2- methylazetidine.
  • Example 126 (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-2-(trifluoromethoxy)benzenesulfonamide
  • the title compound was prepared in a method analogous to General Method F using 5-bromo-2- (trifluoromethoxy)benzenesulfonamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 127 (S)-3-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)phenyl)oxetan-3-ol
  • the title compound was prepared in a method analogous to General Method A using 3-[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxetan-3-ol and (S)-4-chloro-2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 128 (S)-4-(7,7-difluoro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method M, followed by General Method B.
  • Example 129 4-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method M, followed by General Method B using (2S,3R)-2-methylazetidin-3-ol instead of (S)-2-methylazetidine.
  • Example 130 (S)-2,4-difluoro-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide
  • the title compound was prepared in a method analogous to General Method F using 5-bromo- 2,4-difluoro-benzenesulfonamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 131 (S)-3-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)phenyl)oxetan-3-amine
  • the title compound was prepared in a method analogous to General Method A using tert-butyl N-[3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxetan-3-yl]carbamate and (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3- pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by Method I.
  • Example 132 (S)-7-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)quinolin-2(1H)-one
  • the title compound was prepared in a method analogous to General Method A using 7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-quinolin-2-one and (S)-4-chloro-2-(2-methylazetidin- 1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4- dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 133 (S)-3-(7-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)-2-oxoquinolin-1(2H)-yl)propanoic acid
  • (S)-7-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)quinolin-2(1H)-one trifluoroacetic acid salt (20 mg, 0.045 mmol, 1 equiv.)
  • K2CO3 (16 mg, 0.112 mmol, 2.5 equiv.
  • MeCN MeCN
  • the sealed vial was heated to 120 o C for 2 hours, and was then cooled to ambient temperature and concentrated. The resulting residue was dissolved in MeOH (0.5 mL) and NaOH (2M aq., 0.5 mL) was added. The mixture was heated to 60 o C for 20 min. The mixture was cooled to ambient temperature, concentrated, and subjected to HPLC (0.1% TFA in MeCN-0.1% TFA in H 2 O) to give the title compound.
  • Example 134 2-(5-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)-2,3-dihydro-1H-inden-2-yl)acetic acid
  • the title compound was prepared in a method analogous to General Method F using using 2-(5- bromoindan-2-yl)acetic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 135 2-(5-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)-2,3-dihydro-1H-inden-2-yl)acetamide
  • the title compound was prepared in a method analogous to General Method G using 2-(5-(2- ((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydro-1H- inden-2-yl)acetic acid instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid.
  • Example 136 4-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylic acid
  • the title compound was prepared in a method analogous to General Method F using using 4- bromo-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylic acid instead of 6-bromo-1,1- dioxo-1,2-benzothiazol-3-one.
  • Example 137 (1R,1aR*,6aS*)-4-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxamide
  • Example 138 (1S,1aR*,6aS*)-4-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxamide
  • the title compound was prepared in a method analogous to General Method G using 4-(2-((S)- 2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,
  • Example 139 5-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-2,3-dihydro-1H-indene-2-carboxylic acid
  • the title compound was prepared in a method analogous to General Method F using 5- bromoindane-2-carboxylic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 140 5-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-2,3-dihydro-1H-indene-2-carboxamide
  • the title compound was prepared in a method analogous to General Method G using 5-(2-((S)- 2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydro-1H-indene-2- carboxylic acid instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid.
  • Example 141 4-(2-((2S,3R)-3-hydroxy-2,3-dimethylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method B using (2S,3R)- 2,3-dimethylazetidin-3-ol (R)-camphorsulfonic acid salt and 4-(2-chloro-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide instead of (S)-2-methyl azetidine and 2-chloro-4- (pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 142 4-(2-(pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzamide
  • the title compound was prepared in a method analogous to General Method B using pyrrolidine and and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide instead of (S)-2- methyl azetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 143 (S)-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)quinolin-2-amine
  • the title compound was prepared in a method analogous to General Method A using 6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine and (S)-4-chloro-2-(2-methylazetidin-1- yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro- 6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 144 (S)-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-1-naphthamide
  • the title compound was prepared in a method analogous to General Method A using 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthamide and (S)-4-chloro-2-(2-methylazetidin-1- yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro- 6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 145 (3R,4S)-1-acetyl-4-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)pyrrolidine-3-carboxylic acid
  • a vial was charged with methyl (rac)-(3R*,4S*)-4-(3-bromophenyl)pyrrolidine-3-carboxylate (500 mg, 1.56 mmol, 1.0 equiv.), Et 3 N (0.87 mL, 6.24 mmol, 4.0 equiv.), and DCM (10 mL).
  • Example 146 (3R*,4S*)-1-acetyl-4-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)pyrrolidine-3-carboxamide
  • the title compound was prepared in a method analogous to General Method G using (3R*,4S*)- 1-acetyl-4-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)phenyl)pyrrolidine-3-carboxylic acid instead of 2-(3-(2-((2S,3R)-3-hydroxy-2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1- carboxylic acid.
  • Example 147 (S)-7-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)quinazoline-2,4-diamine
  • the title compound was prepared in a method analogous to General Method F using 7- bromoquinazoline-2,4-diamine instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 148 7'-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-2-carboxylic acid
  • the title compound was prepared in a method analogous to General Method F using 7'-bromo- 3',4'-dihydro-2'H-spiro[cyclopropane-1,1'-naphthalene]-2-carboxylic acid instead of 6-bromo- 1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 149 (S)-8-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one
  • the title compound was prepared in a method analogous to General Method A using 8-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one and (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3- pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 150 (S)-7-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one
  • the title compound was prepared in a method analogous to General Method A using 7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one and (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3- pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 151 (S)-4-(1H-indol-2-yl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A using (1-tert- butoxycarbonylindol-2-yl)boronic acid and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively, followed by General Method I.
  • Example 152 (S)-2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-1H-indole-5-carboxamide
  • Example 153 (S)-2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-1H-indole-5-carboxylic acid
  • the title compounds were prepared in a method analogous to General Method A using (1-tert- butoxycarbonyl-5-cyano-indol-2-yl)boronic acid and (S)-4-chloro-2-(2-methylazetidin-1-yl)- 6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7- dihydro-5H-cyclopenta[d]
  • Example 154 (S)-2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-1H-indole-7-carboxamide
  • the title compounds were prepared in a method analogous to General Method A using (1-tert- butoxycarbonyl-7-methoxycarbonyl-indol-2-yl)boronic acid and (S)-4-chloro-2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by General Method I, General Method C, and General Method G.
  • Example 155 (S)-2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-1H-indole-4-carboxylic acid
  • the title compounds were prepared in a method analogous to General Method A using (1-tert- butoxycarbonyl-4-ethoxycarbonyl-indol-2-yl)boronic acid and (S)-4-chloro-2-(2-methylazetidin- 1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4- dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by General Method I and General Method C.
  • Example 156 (S)-2-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-1H-indole-4-carboxamide
  • the title compound was prepared in a method analogous to General Method G using (S)-2-(2- (2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-indole-4-carboxylic acid instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid.
  • Example 157 (S)-4-(8,8-difluoro-2-(2-methylazetidin-1-yl)-5,6,7,8-tetrahydroquinazolin-4- yl)benzamide
  • the title compound was prepared in a method analogous to General Method M using 4-chloro- 8,8-difluoro-2-(methylthio)-5,6,7,8-tetrahydroquinazoline instead of 4-(7,7-difluoro-2- (methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide, followed by General Method B.
  • Example 158 4-(8,8-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-5,6,7,8- tetrahydroquinazolin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method M using 4-chloro- 8,8-difluoro-2-(methylthio)-5,6,7,8-tetrahydroquinazoline instead of 4-(7,7-difluoro-2- (methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide, followed by General Method B using (2S,3R)-2-methylazetidin-3-ol instead of (S)-2-methylazetidine.
  • Example 159 (2S,3R)-1-(4-(4-(3-aminooxetan-3-yl)phenyl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-ol
  • the title compound was prepared in a method analogous to General Method A using tert-butyl (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-yl)carbamate instead of 3- pyridylboronic acid, followed by General Method B using (2S,3R)-2-methylazetidin-3-ol instead of (S)-2-methylazetidine and General Method I.
  • Example 160 (S)-3-(4-(7,7-difluoro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)oxetan-3-amine
  • the title compound was prepared in a method analogous to General Method M using tert-butyl (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-yl)carbamate instead of (4- carbamoylphenyl)boronic acid, followed by General Method B and General Method I.
  • Example 161 (2S,3R)-1-(4-(4-(3-aminooxetan-3-yl)phenyl)-7,7-difluoro-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-ol
  • the title compound was prepared in a method analogous to General Method M using tert-butyl (3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-yl)carbamate instead of (4- carbamoylphenyl)boronic acid, followed by General Method B using (2S,3R)-2-methylazetidin- 3-ol instead of (S)-2-methylazetidine and General Method I.
  • Example 162 4-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzoic acid
  • the title compound was prepared in a method analogous to General Method A using 4- boronobenzoic acid instead of 3-pyridylboronic acid, followed by General Method B using (2S,3R)-2-methylazetidin-3-ol instead of (S)-2-methylazetidine.
  • Example 163 (S)-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)isoquinoline
  • the title compound was prepared in a method analogous to General Method A using 6- isoquinolylboronic acid and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 164 8-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one
  • the title compound was prepared in a method analogous to General Method A using 8-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one instead of 3- pyridylboronic acid, followed by General Method B using (2S,3R)-2-methylazetidin-3-ol instead of (S)-2-methylazetidine.
  • Example 165 (S)-8-(7,7-difluoro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one
  • the title compound was prepared in a method analogous to General Method M using 8-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one instead of (4- carbamoylphenyl)boronic acid, followed by General Method B.
  • Example 166 8-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one
  • the title compound was prepared in a method analogous to General Method M using 8-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one instead of (4- carbamoylphenyl)boronic acid, followed by General Method B using (2S,3R)-2-methylazetidin- 3-ol instead of (S)-2-methylazetidine.
  • Example 167 (S)-4-(2-(1-methylisoindolin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzamide
  • the title compound was prepared in a method analogous to General Method B using (S)-1- methylisoindoline and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide instead of (S)-2-methyl azetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 168 5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)picolinamide
  • the title compound was prepared in a method analogous to General Method M using 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide instead of (4-carbamoylphenyl)boronic acid, followed by General Method B using (2S,3R)-2-methylazetidin-3-ol instead of (S)-2- methylazetidine.
  • Example 169 4-(2-((2S,3S)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method A using (4- carbamoylphenyl)boronic acid instead of 3-pyridylboronic acid, followed by General Method B using (2S,3S)-2-methylazetidin-3-ol instead of (S)-2-methylazetidine.
  • Example 170 4-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2-ethoxybenzamide
  • the title compound was prepared in a method analogous to General Method M using 2-ethoxy- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide instead of (4- carbamoylphenyl)boronic acid, followed by General Method B using (2S,3R)-2-methylazetidin- 3-ol instead of (S)-2-methylazetidine.
  • Example 171 4-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-N-methylbenzamide
  • the title compound was prepared in a method analogous to General Method M using N-methyl- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide instead of (4- carbamoylphenyl)boronic acid, followed by General Method B using (2S,3R)-2-methylazetidin- 3-ol instead of (S)-2-methylazetidine.
  • Example 172 4-(2-(4-(hydroxymethyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method A using (4- carbamoylphenyl)boronic acid instead of 3-pyridylboronic acid, followed by General Method B using (2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-4-yl)methanol instead of (S)-2-methylazetidine.
  • Example 173 4-(2-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared according to General Method N.
  • Example 174 4-(2-(2,3-dihydro-1H-imidazo[1,5-a]imidazol-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method N, using 2,3- dihydro-1H-imidazo[1,5-a]imidazole instead of 2,3-dihydro-1H-imidazo[1,2-b]pyrazole.
  • Example 175 (S)-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)quinolin-2-ol
  • the title compound was prepared in a method analogous to General Method A, using 6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-ol and (S)-4-chloro-2-(2-methylazetidin-1-yl)- 6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7- dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 176 4-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-5,7- methanocyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method H, using ethyl 3- oxobicyclo[2.1.1]hexane-2-carboxylate and (3-carbamoylphenyl)boronic acid instead of methyl 2-oxobicyclo[3.1.0]hexane-3-carboxylate and (4-carbamoylphenyl)boronic acid, respectively.
  • Example 177 4-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2-methoxybenzamide
  • the title compound was prepared in a method analogous to General Method M using 2- methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide instead of (4- carbamoylphenyl)boronic acid, followed by General Method B using (2S,3R)-2-methylazetidin- 3-ol instead of (S)-2-methylazetidine.
  • Example 178 7-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one
  • the title compound was prepared in a method analogous to General Method D, using 7-bromo- 2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one instead of ethyl 2-bromoimidazo[5,1-b]thiazole-7- carboxylate, followed by General Method E using 4-chloro-7,7-difluoro-2-(methylthio)-6,7- dihydro-5H-cyclopenta[d]pyrimidine instead of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d
  • Example 179 (S)-8-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-3-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one
  • the title compound was prepared according to General Method Q, followed by General Method F, using (S)-8-bromo-3-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one and 4-chloro-7,7- difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 6-bromo-1,1-dioxo- 1,2-benzothiazol-3-one and (S)-4-chloro-2-(2-methylazetidin-1-yl)
  • Example 180 (R)-8-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-methyl-3,4-dihydrobenzo[f][1,4]oxazepin- 5(2H)-one
  • the title compound was prepared in a method analogous to General Method Q, using tert-butyl (R)-(1-hydroxypropan-2-yl)carbamate instead of tert-butyl (S)-(1-hydroxypropan-2- yl)carbamate, followed by General Method F, using (R)-8-bromo-3-methyl-3,4- dihydrobenzo[f][1,4]oxazepin-5(2H)-one and 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro- 5H-cycl
  • Example 181 2-acetamido-4-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)- 6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method M using 2- acetamido-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamideinstead of (4- carbamoylphenyl)boronic acid, followed by General Method B using (2S,3R)-2-methylazetidin- 3-ol instead of (S)-2-methylazetidine.
  • Example 182 4-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2-(difluoromethoxy)benzamide
  • the title compound was prepared in a method analogous to General Method F, using methyl 4- bromo-2-(difluoromethoxy)benzoate and 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H- cyclopenta[d]pyrimidine instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one and (S)-4-chloro- 2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, followed by General Method M using methyl 4-(7,7-difluoro-2
  • Example 183 4-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2-(trifluoromethoxy)benzamide
  • the title compound was prepared in a method analogous to General Method M using methyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethoxy)benzoate instead of (4- carbamoylphenyl)boronic acid, followed by General Method B using (2S,3R)-2-methylazetidin- 3-ol instead of (S)-2-methylazetidine, followed by General Method C and General Method G.
  • Example 184 5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]-1H-indole-2-carboxamide
  • the title compound was prepared in a method analogous to General Method A using 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carboxamide and (S)-4-chloro-2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 185 4-[4-(1H-imidazol-2-yl)phenyl]-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro- 5H-cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A using 2-(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazole and (S)-4-chloro-2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 186 2-methyl-5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]isoindolin-1-one
  • the title compound was prepared in a method analogous to General Method A using 2-methyl- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one and (S)-4-chloro-2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 187 5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]isoindolin-1-one
  • the title compound was prepared in a method analogous to General Method A using 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one and (S)-4-chloro-2-(2-methylazetidin-1- yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro- 6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 188 [4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]phenyl]methanamine
  • the title compound was prepared in a method analogous to General Method A using using (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine and (S)-4-chloro-2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 189 4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]benzenesulfonamide
  • the title compound was prepared in a method analogous to General Method A using 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide and (S)-4-chloro-2-(2-methylazetidin- 1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4- dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 190 2-[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl]phenyl]propan-2-amine
  • the title compound was prepared in a method analogous to General Method A using 2-(3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-amine and (S)-4-chloro-2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 191 4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]benzamide
  • the title compound was prepared in a method analogous to General Method A using using 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide and (S)-4-chloro-2-(2-methylazetidin- 1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4- dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 192 3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]benzenesulfonamide
  • the title compound was prepared in a method analogous to General Method A using 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide and (S)-4-chloro-2-(2-methylazetidin- 1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4- dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 193 (2S,3R)-1-[4-[4-(1H-imidazol-2-yl)phenyl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl]-2-methyl-azetidin-3-ol
  • the title compound was prepared in a method analogous to General Method A using 2-(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazole hydrochloride salt instead of 3-pyridylboronic acid, followed by General Method B using (2S,3R)-2-methylazetidin-3-ol instead of (2S)-2-methylazetidine.
  • Example 194 5-[2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-2-methyl-isoindolin-1-one
  • the title compound was prepared in a method analogous to General Method A using 2-methyl- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one instead of 3-pyridylboronic acid, followed by General Method B using (2S,3R)-2-methylazetidin-3-ol hydrochloride salt instead of (2S)-2-methylazetidine.
  • Example 195 N-[[4-[2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]methanesulfonamide
  • the title compound was prepared in a method analogous to General Method A using (4- (methylsulfonamidomethyl)phenyl)boronic acid instead of 3-pyridylboronic acid, followed by General Method B using (2S,3R)-2-methylazetidin-3-ol hydrochloride salt instead of (2S)-2- methylazetidine.
  • Example 196 5-[2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]isoindolin-1-one
  • the title compound was prepared in a method analogous to General Method A using 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one instead of 3-pyridylboronic acid, followed by General Method B using (2S,3R)-2-methylazetidin-3-ol hydrochloride salt instead of (2S)-2- methylazetidine.
  • Example 197 4-[2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]benzamide
  • the title compound was prepared in a method analogous to General Method A using (4- carbamoylphenyl)boronic acid instead of 3-pyridylboronic acid, followed by General Method B using (2S,3R)-3-fluoro-2-methylazetidine hydrochloride salt instead of (2S)-2-methylazetidine.
  • Example 198 4-[2-[(2S,3R)-3-fluoro-2-methyl-azetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide
  • the title compound was prepared in a method analogous to General Method A using (4- sulfamoylphenyl)boronic acid instead of 3-pyridylboronic acid, followed by General Method B using (2S,3R)-3-fluoro-2-methylazetidine hydrochloride salt instead of (2S)-2-methylazetidine.
  • Example 199 4-[2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide
  • the title compound was prepared in a method analogous to General Method A using (4- sulfamoylphenyl)boronic acid instead of 3-pyridylboronic acid, followed by General Method B (2S,3R)-2-methylazetidin-3-ol hydrochloride salt instead of (2S)-2-methylazetidine.
  • Example 200 4-[2-[(2S,3R)-3-fluoro-2-methyl-azetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]benzamide
  • the title compound was prepared in a method analogous to General Method A using (4- carbamoylphenyl)boronic acid instead of 3-pyridylboronic acid, followed by General Method B using (2S,3R)-3-fluoro-2-methylazetidine hydrochloride salt instead of (2S)-2-methylazetidine.
  • Example 201 [4-[2-[(2S,3R)-3-fluoro-2-methyl-azetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]methanamine
  • the title compound was prepared in a method analogous to General Method A using (4- (aminomethyl)phenyl)boronic acid hydrochloride instead of 3-pyridylboronic acid, followed by General Method B using (2S,3R)-3-fluoro-2-methylazetidine hydrochloride salt instead of (2S)- 2-methylazetidine.
  • Example 202 (2S,3R)-1-[4-[4-(aminomethyl)phenyl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl]-2-methyl-azetidin-3-ol
  • the title compound was prepared in a method analogous to General Method A using (4- (aminomethyl)phenyl)boronic acid hydrochloride instead of 3-pyridylboronic acid, followed by General Method B (2S,3R)-2-methylazetidin-3-ol hydrochloride salt instead of (2S)-2- methylazetidine.
  • Example 203 6-[2-[(2S,3R)-3-fluoro-2-methyl-azetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-2-methyl-isoindolin-1-one
  • the title compound was prepared in a method analogous to General Method A using 2-methyl- 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one instead of 3-pyridylboronic acid, followed by General Method B using (2S,3R)-3-fluoro-2-methylazetidine hydrochloride salt instead of (2S)-2-methylazetidine.
  • Example 204 6-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-methyl- isoindolin-1-one
  • the title compound was prepared in a method analogous to General Method A using 2-methyl- 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one instead of 3-pyridylboronic acid, followed by General Method B using (2S,3R)-2-methylazetidin-3-ol hydrochloride salt instead of (2S)-2-methylazetidine.
  • Example 205 5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]pyridine-3-sulfonamide
  • the title compound was prepared in a method analogous to General Method A using 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide instead of 3-pyridylboronic acid, followed by General Method B.
  • Example 206 2-methyl-6-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]isoindolin-1-one
  • the title compound was prepared in a method analogous to General Method A using 2-methyl- 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one instead of 3-pyridylboronic acid, followed by General Method B.
  • Example 207 6-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)isoindolin-1-one
  • the title compound was prepared in a method analogous to General Method A using (3- oxoisoindolin-5-yl)boronic acid instead of 3-pyridylboronic acid, followed by General Method B.
  • Example 208 3-[2-[(2S,4S)-2,4-dimethylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide
  • the title compound was prepared in a method analogous to General Method A using 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide instead of 3-pyridylboronic acid, followed by General Method B using (2S,4S)-2,4-dimethylazetidine hydrochloride salt instead of (2S)-2-methylazetidine.
  • Example 209 3-[2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide
  • the title compound was prepared in a method analogous to General Method A using 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide instead of 3-pyridylboronic acid, followed by General Method B using (2S,3R)-2-methylazetidin-3-ol hydrochloride salt instead of (2S)-2-methylazetidine.
  • Example 210 3-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzenesulfonamide
  • the title compound was prepared in a method analogous to General Method A using 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide instead of 3-pyridylboronic acid, followed by General Method B using (2S,3R)-3-fluoro-2-methylazetidine hydrochloride salt instead of (2S)-2-methylazetidine.
  • Example 211 7-methyl-2-[(2S)-2-methylazetidin-1-yl]-6-phenyl-purine
  • the title compound was prepared in a method analogous to General Method A using phenylboronic acid and 2,6-dichloro-7-methyl-7H-purine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by General Method B.
  • Example 212 2-[(2S)-2-methylazetidin-1-yl]-4-phenyl-pyrido[2,3-d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A using phenylboronic acid and 2,4-dichloropyrido[2,3-d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by General Method B.
  • Example 213 2-[5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl]thiazol-2-yl]propan-2-ol
  • the title compound was prepared in a method analogous to General Method E using 2-(5- (tributylstannyl)thiazol-2-yl)propan-2-ol instead of with ethyl 2-tributylstannylimidazo[5,1- b]thiazole-7-carboxylate.
  • Example 214 N-methyl-3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide 3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]benzenesulfonamide (42 mg, 0.12 mmol) was dissolved in DMF (10.5 mL) and then cooled to 0 o C over 20 mins.
  • Example 215 N,N-dimethyl-3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]benzenesulfonamide 3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]benzenesulfonamide (42 mg, 0.12 mmol) was dissolved in DMF (10.5 mL) and then cooled to 0 o C over 20 mins.
  • reaction mixture was cooled to 0 o C, slowly quenched with water, extracted with EtOAc, dried, filtered, concentrated and purified on the HPLC (0.1% TFA in MeCN-0.1% TFA in H 2 O) to provide N,N-dimethyl-3- [2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]benzenesulfonamide.
  • Example 216 N-(2-amino-2-oxo-ethyl)-3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]benzamide
  • the title compound was prepared in a method analogous to General Method G using 3- aminopropanoic acid and (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzoic acid instead of ammonia and 2-(3-(2-((2S,3R)-3-hydroxy- 2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1- carboxylic acid, respectively.
  • Example 217 3-[[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]benzoyl]amino]propanoic acid
  • the title compound was prepared in a method analogous to General Method G using 3- aminopropanoic acid and (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzoic acid instead of ammonia and 2-(3-(2-((2S,3R)-3-hydroxy- 2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1- carboxylic acid, respectively.
  • Example 218 N-benzyl-3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]benzamide
  • the title compound was prepared in a method analogous to General Method G using benzylamine and (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzoic acid instead of ammonia and 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)- 6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid, respectively.
  • Example 219 3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]-N-(2-sulfamoylethyl)benzamide
  • the title compound was prepared in a method analogous to General Method G using 2- aminoethane-1-sulfonamide and (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzoic acid instead of ammonia and 2-(3-(2-((2S,3R)-3-hydroxy- 2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1- carboxylic acid, respectively.
  • Example 220 N-(3-amino-3-oxo-propyl)-3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]benzamide
  • the title compound was prepared in a method analogous to General Method G using 3- aminopropanamide and (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzoic acid instead of ammonia and 2-(3-(2-((2S,3R)-3-hydroxy- 2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1- carboxylic acid, respectively.
  • Example 221 (S)-(5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)thiazol-2-yl)methanamine
  • the title compound was prepared in a method analogous to General Method D, using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 2- bromoimidazo[5,1-b]thiazole-7-carboxylate, followed by General Method E using tert-butyl N- [(5-bromothiazol-2-yl)methyl]carbamate instead of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidine and General Method I.
  • Example 222 (S)-2-methyl-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one
  • the title compound was prepared in a method analogous to General Method D, using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 2- bromoimidazo[5,1-b]thiazole-7-carboxylate, followed by General Method E using 6-bromo-2- methyl-3,4-dihydroisoquinolin-1(2H)-one instead of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidine.
  • Example 223 (S)-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)pyridine-2-sulfonamide
  • the title compound was prepared in a method analogous to General Method D, using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 2- bromoimidazo[5,1-b]thiazole-7-carboxylate, followed by General Method E using 6- bromopyridine-2-sulfonamide instead of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidine.
  • Example 224 (S)-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)pyridine-2-sulfonamide
  • the title compound was prepared in a method analogous to General Method D, using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 2- bromoimidazo[5,1-b]thiazole-7-carboxylate, followed by General Method E using 4- bromopyridine-2-sulfonamide instead of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidine.
  • Example 225 (S)-1-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)phenyl)cyclopropan-1-amine
  • the title compound was prepared in a method analogous to General Method D, using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 2- bromoimidazo[5,1-b]thiazole-7-carboxylate, followed by General Method E using 1-(3- bromophenyl)cyclopropan-1-amine instead of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidine.
  • Example 226 4-(2-((2S,3S)-3-fluoro-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • a vial was charged with 4-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide (23.5 mg, 0.0.72 mmols) and DCM (0.24 mL).
  • DAST 117 mg, 0.72 mmols
  • reaction mixture was slowly quenched with ice chips to 0 o C, extracted with 25% MeOH/DCM, washed with NaHCO3 (aq., sat.), dried over Na2SO4, filterer and concentrated. The residue was subjected to HPLC HPLC (0.1% TFA in MeCN-0.1% TFA in H 2 O) to give the title compound.
  • Example 227 3-hydroxy-N-[[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]propanamide
  • the title compound was prepared in a method analogous to General Method G using 3- hydroxypropanoic acid and (S)-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)methanamine instead of 2-(3-(2-((2S,3R)-3-hydroxy-2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1- carboxylic acid and ammonia, respectively.
  • Example 228 2-hydroxy-2-methyl-N-[[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]propanamide
  • the title compound was prepared in a method analogous to General Method G using 2-hydroxy- 2-methylpropanoic acid and (S)-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)methanamine instead of 2-(3-(2-((2S,3R)-3-hydroxy-2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1- carboxylic acid and ammonia, respectively.
  • Example 229 (2R)-2-hydroxy-N-[[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]propanamide
  • the title compound was prepared in a method analogous to General Method G using (R)-2- hydroxypropanoic acid and (S)-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)methanamine instead of 2-(3-(2-((2S,3R)-3-hydroxy-2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1- carboxylic acid and ammonia, respectively.
  • Example 230 (2S)-2-hydroxy-N-[[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]propanamide
  • the title compound was prepared in a method analogous to General Method G using (S)-2- hydroxypropanoic acid and (S)-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)methanamine instead of 2-(3-(2-((2S,3R)-3-hydroxy-2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1- carboxylic acid and ammonia, respectively.
  • Example 231 2-hydroxy-N-[[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]acetamide
  • the title compound was prepared in a method analogous to General Method G using 2- hydroxyacetic acid and (S)-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)methanamine instead of 2-(3-(2-((2S,3R)-3-hydroxy-2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1- carboxylic acid.
  • Example 232 7-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]naphthalene-2-carboxylic acid
  • the title compound was prepared in a method analogous to General Method F using 7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthoic acid instead of 6-bromo-1,1-dioxo-1,2- benzothiazol-3-one.
  • Example 233 4-[4-(azetidin-3-yl)phenyl]-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method F using tert-butyl 3- (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine-1-carboxylate instead of 6- bromo-1,1-dioxo-1,2-benzothiazol-3-one, followed by General Method I.
  • Example 234 7-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]-1,1-dioxo-2,3-dihydro-1lambda6,3-benzothiazin-4-one
  • the title compound was prepared in a method analogous to General Method D using 7-bromo- 2,3-dihydro-4H-benzo[e][1,3]thiazin-4-one 1,1-dioxide instead of 2-bromoimidazo[5,1- b]thiazole-7-carboxylate, followed by General Method E.
  • Example 235 4-(2-((2S,3R)-3-methoxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • (2S,3R)-1-(4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2- methylazetidin-3-ol 21 mg, 0.09 mmoles
  • DMF (1 mL)
  • reaction mixture was allowed to stir at 0 o C for 20 mins and then MeI (14.9 mg , 0.11 mmoles) was slowly added and the reaction mixture was allowed to warm to ambient over 15 mins.
  • the reaction mixture was cooled to 0 o C, quenched with ice water, and extracted with DCM (3 x 1 mL). The combined organics were dried over Na 2 SO 4 , filtered, and concentrated to provide 4-(2-((2S,3R)-3- methoxy-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide, which was used without any further purifications.
  • the title compound was prepared in a method analogous to General Method A using 4-chloro-2- [(2S,3R)-3-methoxy-2-methyl-azetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine and (4- carbamoylphenyl)boronic acid instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 236 6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2-methylisoindolin-1-one
  • the title compound was prepared in a method analogous to General Method A using 4-chloro- 7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 2-methyl-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one instead of 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine and 3-pyridylboronic acid, followed by General Method M and General Method B, using (2S,3R)-2-methylazetidin-3-ol instead of (2S)-2
  • Example 237 (S)-2-amino-1-(5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-1H-indazol-1-yl)ethan-1-one
  • Example 238 (S)-2-amino-1-(5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2H-indazol-2-yl)ethan-1-one
  • a vial was charged with (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-1H-indazole (28 mg, 0.092 mmoL), potassium carbonate (50.2 mg, 0.37 mmol), and MeCN (0.7 mL).
  • Example 239 (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide
  • the title compound was prepared in a method analogous to General Method F using 5- bromobenzo[d]isothiazol-3(2H)-one 1,1-dioxide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol- 3-one.
  • Example 240 5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]isoindoline-1,3-dione
  • the title compound was prepared in a method analogous to General Method F using 5- bromoisoindoline-1,3-dione instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 241 6-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]-2-(trifluoromethyl)-1H-benzimidazole
  • the title compound was prepared in a method analogous to General Method F using 6-bromo-2- (trifluoromethyl)-1H-benzimidazole instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 242 [4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]phenyl]methanesulfonamide
  • the title compound was prepared in a method analogous to General Method F using (4- bromophenyl)methanesulfonamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 243 5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]-3-(trifluoromethyl)-1H-indazole
  • the title compound was prepared in a method analogous to General Method F using 5-bromo-3- (trifluoromethyl)-1H-indazole instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 244 2-[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl]phenyl]acetamide
  • the title compound was prepared in a method analogous to general method F using 2-(3- bromophenyl)acetamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 245 2-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl]phenyl]acetamide
  • the title compound was prepared in a method analogous to General Method F using 2-(4- bromophenyl)acetamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 246 2,2,2-trifluoro-1-[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]ethanamine
  • the title compound was prepared in a method analogous to General Method F using 1-(3- bromophenyl)-2,2,2-trifluoro-ethanamine instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 247 5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]-1,3-dihydrobenzimidazol-2-one
  • the title compound was prepared in a method analogous to General Method F using 5-bromo- 1,3-dihydrobenzimidazol-2-one instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 248 5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]indolin-2-one
  • the title compound was prepared in a method analogous to General Method F using 5- bromoindolin-2-one instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one
  • Example 249 3-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl]phenyl]bicyclo[1.1.1]pentane-1-carboxylic acid
  • the title compound was prepared in a method analogous to General Method F using 3-(4- bromophenyl)bicyclo[1.1.1]pentane-1-carboxylic acid instead of 6-bromo-1,1-dioxo-1,2- benzothi
  • Example 250 3-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl]phenyl]bicyclo[1.1.1]pentane-1-carboxamide
  • the title compound was prepared in a method analogous to General Method F using 3-(4- bromophenyl)bicyclo[1.1.1]pentane-1-carboxamide instead of 6-bromo-1,1-dioxo-1,2- benzothiazol-3-one.
  • Example 251 3-methyl-5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta [d]pyrimidin-4-yl]-1H-benzimidazol-2-one
  • the title compound was prepared in a method analogous to General Method F using 5-bromo-3- methyl-1H-benzimidazol-2-one instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 252 1-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl]phenyl]cyclopropanecarboxamide
  • the title compound was prepared in a method analogous to General Method F using 1-(4- bromophenyl)cyclopropanecarboxamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 253 1-[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl]phenyl]cyclopropanecarboxylic acid
  • the title compound was prepared in a method analogous to General Method F using 1-(3- bromophenyl)cyclopropanecarboxylic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3- one.
  • Example 254 1-[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl]phenyl]cyclopropanecarboxamide
  • the title compound was prepared in a method analogous to General Method F using 1-(3- bromophenyl)cyclopropanecarboxamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 255 1-[hydroxy-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]cyclopropanecarbonitrile
  • the title compound was prepared in a method analogous to General Method A using 1- [hydroxy-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]methyl]cyclopropanecarbonitrile and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7- dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 256 2,2-difluoro-1-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]ethanol
  • the title compound was prepared in a method analogous to General Method A using 2,2- difluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanol and (S)-4-chloro-2- (2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 257 2-fluoro-1-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]ethanol
  • the title compound was prepared in a method analogous to General Method A using 2-fluoro-1- [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanol and (S)-4-chloro-2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 258 4-[3-(difluoromethoxy)phenyl]-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro- 5H-cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A using 2-[3- (difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and (S)-4-chloro-2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 259 4-[1-(difluoromethyl)pyrazol-4-yl]-2-[(2S)-2-methylazetidin-1-yl]-6,7- dihydro-5H-cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A using 1- (difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole and (S)-4-chloro-2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 260 2-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]phenol
  • the title compound was prepared in a method analogous to General Method A using (2- hydroxyphenyl)boronic acid and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 261 3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]phenol
  • the title compound was prepared in a method analogous to General Method A using (3- hydroxyphenyl)boronic acid and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 262 4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]phenol
  • the title compound was prepared in a method analogous to General Method A using (4- hydroxyphenyl)boronic acid and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 263 7-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine
  • the title compound was prepared in a method analogous to General Method A using 7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine and (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3- pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 264 3,3-dimethyl-6-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]indolin-2-one
  • the title compound was prepared in a method analogous to General Method A using 3,3- dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one and (S)-4-chloro-2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 265 2,2,2-trifluoro-1-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]ethanol
  • the title compound was prepared in a method analogous to General Method A using 2,2,2- trifluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanol and (S)-4-chloro-2- (2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 266 (rac)-(2S*,3R*)-1-(4-(4-carbamoylphenyl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)-2-methylazetidine-3-carboxamide
  • the title compound was prepared in a method analogous to General Method B using trans-2- methylazetidine-3-carbonitrile and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzamide instead of (S)-2-methyl azetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 267 (rac)-4-(2-((2S*,3R*)-3-(hydroxymethyl)-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method B using (trans-2- methylazetidin-3-yl)methanol and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzamide instead of (S)-2-methyl azetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 268 4-[2-[(3S)-3-hydroxy-3-methyl-pyrrolidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]benzamide
  • the title compound was prepared in a method analogous to General Method B using (3S)-3- methylpyrrolidin-3-ol instead of (S)-2-methyl azetidine and 2-chloro-4-(pyridin-3-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 269 2,2,2-trifluoro-1-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]ethanamine N-[2,2,2-trifluoro-1-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl]phenyl]ethyl]acetamide was formed in a method analogous to General Method A using N- (2,2,2-trifluoro-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)acetamide and (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead
  • Example 270 4-(3-((1S*,2S*)-2-(2H-tetrazol-5-yl)cyclopropyl)phenyl)-2-((S)-2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine
  • a vial was charged with trans-2-[3-[2-[rel-(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]cyclopropanecarbonitrile (15.8 mg, 0.048 mmol, 1.0 equiv.), trimethyltin azide (19.9 mg, 0.096 mmol, 2.0 equiv.) and xylene (2.0 mL) The reaction mixture was stirred at 150°C for 18 hrs before being cooled to ambient temperature and concentrated.
  • Example 271 (S)-3-(1-methyl-5-(2-methylazetidin-1-yl)-1H-pyrazolo[4,3-d]pyrimidin-7- yl)benzamide
  • the title compound was prepared in a method analogous to General Method A using 5,7- dichloro-1-methyl-1H-pyrazolo[4,3-d]pyrimidine and 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively, followed by General Method B.
  • Example 272 3-(2-((S)-2-methylazetidin-1-yl)-5,5a,6,6a- tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidin-4-yl)benzamide
  • the title compound was prepared according to General Method H.
  • Example 273 5-(2-((S)-2-methylazetidin-1-yl)-5,5a,6,6a- tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidin-4-yl)isothiazole
  • the title compound was prepared in a method analogous to General Method H using 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazole instead of 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide.
  • Example 274 (S)-4-(2,3-dihydrobenzofuran-5-yl)-2-(2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 2,3- dihydrobenzofuran-5-yl-boronic acid instead of 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 275 (S)-4-(1-methyl-1H-indol-5-yl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 1-methylindol-5- yl-boronic acid instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3- pyridylboronic acid, respectively.
  • Example 276 1-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)phenyl)ethan-1-ol
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-(1- hydroxyethyl)phenyl-boronic acid instead of 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 277 (S)-N-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)benzyl)methanesulfonamide
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3- (methanesulfonamidomethyl)phenyl boronic acid instead of 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 278 (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)pyridin-2-amine
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine instead of 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 279 (S)-4-(3-(1H-pyrazol-5-yl)phenyl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-(1H-pyrazol-5- yl)phenylboronic acid instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3- pyridylboronic acid, respectively.
  • Example 280 (S)-N-methyl-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)picolinamide
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and N-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide instead of 2,4-dichloro- 6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 281 (S)-4-(2-fluoropyridin-4-yl)-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine instead of 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 282 (S)-2-((4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)pyridin-2-yl)amino)ethan-1-ol
  • the title compound was prepared by heating (S)-4-(2-fluoropyridin-4-yl)-2-(2-methylazetidin-1- yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (22 mg, 0.07 mmol) in ethanolamine (2 mL) in the microwave at 150 oC for 30 minutes.
  • Example 283 (S)-6-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-3,4-dihydroisoquinolin-1(2H)-one
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-isoquinolin-1-one instead of 2,4-dichloro- 6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 284 N-(3-(2-((2S,3R)-3-fluoro-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzyl)methanesulfonamide
  • the title compound was prepared in a method analogous to General Method A using 3- (methanesulfonamidomethyl)phenylboronic acid and General Method B using (2S,3R)-3-fluoro- 2-methyl-azetidine instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3- pyridylboronic acid, respectively.
  • Example 285 N-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzyl)methanesulfonamide
  • the title compound was prepared in a method analogous to General Method A using 3- (methanesulfonamidomethyl)phenylboronic acid instead of 3-pyridylboronic acid and General Method B using (2S,3R)-2-methylazetidin-3-ol instead of (2S)-2-methylazetidine.
  • Example 286 3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,8-dihydro-5H-pyrano[3,4- d]pyrimidin-4-yl)benzenesulfonamide
  • the title compound was prepared in a method analogous to General Method A using 2,4- dichloro-6,8-dihydro-5H-pyrano[3,4-d]pyrimidine and 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 288 6-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one
  • the title compound was prepared in a method analogous to General Method A using 6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-isoquinolin-1-one instead of 3- pyridylboronic acid followed by General Method B using (2S,3R)-2-methylazetidin-3-ol instead of (2S)-2-methylazetidine.
  • Example 289 6-(2-((2S,3R)-3-fluoro-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-3,4-dihydroisoquinolin-1(2H)-one
  • the title compound was prepared in a method analogous to General Method A using 6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-isoquinolin-1-one instead of 3- pyridylboronic acid, followed by General Method B using (2S,3R)-3-fluoro-2-methyl-azetidine instead of (2S)-2-methylazetidine.
  • Example 290 N-(3-(2-((2S,3R)-3-fluoro-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)methanesulfonamide
  • the title compound was prepared in a method analogous to General Method A using 3- (methanesulfonamido)phenylboronic acid instead of 3-pyridylboronic acid, followed by General Method B using (2S,3R)-3-fluoro-2-methyl-azetidine instead of (2S)-2-methylazetidine.
  • Example 291 (S)-4-(5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)pyridin-2-yl)morpholine
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 6-morpholino-3- pyridylboronic acid instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3- pyridylboronic acid, respectively.
  • Example 292 (S)-N-methyl-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and N-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide instead of 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 293 (S)-N,N-dimethyl-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and N,N-dimethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide instead of 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 294 (S)-tert-butyl (1-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropyl)carbamate
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 4-[1-(tert- butoxycarbonylamino)cyclopropyl]phenyl boronic acid instead of 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 295 (S)-1-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)phenyl)cyclopropan-1-amine
  • the title compound was prepared according to General Method I using (S)-tert-butyl (1-(4-(2- (2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)phenyl)cyclopropyl)carbamate instead of tert-butyl (S)-4-(4-(2-(2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)piperazine-1-carboxylate.
  • Example 296 (S)-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-N-phenylbenzamide
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid instead of 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively followed by General Method G using aniline instead of ammonia.
  • Example 297 (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-N-phenylbenzamide
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid instead of 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively followed by General Method G using aniline instead of ammonia.
  • Example 298 (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-5-nitrobenzamide
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-carbamoyl-5- nitro-phenylboronic acid instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 300 (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-5-(methylsulfonamido)benzamide
  • the title compound was prepared in a method analogous to General Method K using (S)-3- amino-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide and methanesulfonyl chloride instead of (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)aniline and 1-methylimidazole-4-sulfonyl chloride, respectively.
  • Example 301 (2S,3R)-1-(4-(4-(1-aminocyclopropyl)phenyl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-ol
  • the title compound was prepared in a method analogous to General Method A using 4-[1-(tert- butoxycarbonylamino)cyclopropyl]phenyl boronic acid instead of 3-pyridylboronic acid, followed by General Method B using (2S,3R)-2-methylazetidin-3-ol instead of (2S)-2- methylazetidine then General Method I.
  • Example 302 (S)-2-(2-methylazetidin-1-yl)-4-(4-(1-(4-methylpiperazin-1- yl)cyclopropyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 1-methyl-4-[1- [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl]piperazine instead of 2,4- dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 303 (S)-2-chloro-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 4-carbamoyl-3- chloro-phenylboronic acid instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 304 (S)-4-(1-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropyl)morpholine
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 4-[1-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl]morpholine instead of 2,4-dichloro-6,7- dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 305 (S)-2-fluoro-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 4-carbamoyl-3- fluoro-phenylboronic acid instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 306 (S)-N-(1-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropyl)methanesulfonamide
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and N-[1-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl]methanesulfonamide instead of 2,4- dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 307 2-fluoro-4-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method A using 4- carbamoyl-3-fluoro-phenylboronic acid instead of 3-pyridylboronic acid followed by General Method B using (2S,3R)-2-methylazetidin-3-ol instead of (2S)-2-methylazetidine.
  • Example 308 2-chloro-4-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method A using 4- carbamoyl-3-chloro-phenylboronic acid instead of 3-pyridylboronic acid followed by General Method B using (2S,3R)-2-methylazetidin-3-ol instead of (2S)-2-methylazetidine.
  • Example 309 (S)-2-methoxy-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 4-carbamoyl-3- methoxy-phenylboronic acid instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 310 (S)-2-methoxy-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzonitrile
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 2-methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile instead of 2,4-dichloro-6,7-dihydro- 5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 311 (S)-tert-butyl (1-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)cyclobutyl)carbamate
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and tert-butyl N-[1- [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl]carbamate instead of 2,4- dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 312 (S)-1-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)phenyl)cyclobutan-1-amine
  • the title compound was prepared in a method analogous to General Method I using (S)-tert- butyl (1-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)phenyl)cyclobutyl)carbamate instead of tert-butyl (S)-4-(4-(2-(2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)piperazine-1-carboxylate.
  • Example 313 (S)-2-fluoro-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzonitrile
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile instead of 2,4-dichloro-6,7-dihydro- 5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 314 (S)-2-chloro-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzonitrile
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 2-chloro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile instead of 2,4-dichloro-6,7-dihydro- 5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 315 (S)-2,6-difluoro-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 4-carbamoyl- 3,5-difluoro-phenylboronic acid instead of 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 316 (S)-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-2-(trifluoromethyl)benzamide
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzamide instead of 2,4-dichloro-6,7- dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 317 (S)-6-(7,7-difluoro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)isoquinolin-1(2H)-one
  • the title compound was prepared in a method analogous to General Method H using 4-chloro- 7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 4-chloro-2- (methylthio)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidine and using 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1(2H)-one instead of 3- carbamoylphenylboronic acid.
  • Example 318 6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)isoquinolin-1(2H)-one
  • the title compound was prepared in a method analogous to General Method H using 4-chloro- 7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 4-chloro-2- (methylthio)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidine and using 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1(2H)-one instead of 3- carbamoylphenylboronic acid.
  • (2S,3R)-2-methylazetidin-3-ol hydrochloride salt was used instead of (2S)-2-methylazetidine (R)-camphorsulfonic acid salt.
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 2-ethoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide instead of 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 320 (S)-4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-2-(methylsulfonamido)benzamide
  • the title compound was prepared in a method analogous to General Method A using (S)-4- chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-amino-4- carbamoyl-phenylboronic acid instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively, followed by General Method K using methanesulfonyl chloride instead of 1-methylimidazole-4-sulfonyl chloride.
  • Example 321 (S)-3-(7,7-difluoro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide
  • the title compound was prepared in a method analogous to General Method H using 4-chloro- 7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 4-chloro-2- (methylthio)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidine and using 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide instead of 3- carbamoylphenylboronic acid.
  • Example 322 3-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide
  • the title compound was prepared in a method analogous to General Method H using 4-chloro- 7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 4-chloro-2- (methylthio)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidine and using 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide instead of 3- carbamoylphenylboronic acid.
  • (2S,3R)-2-methylazetidin-3-ol hydrochloride salt was used instead of (2S)-2-methylazetidine (R)-camphorsulfonic acid salt.
  • Example 323 (S)-N-(3-(7,7-difluoro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzyl)methanesulfonamide
  • the title compound was prepared in a method analogous to General Method H using 4-chloro- 7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 4-chloro-2- (methylthio)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidine and using 3- (methanesulfonamidomethyl)phenyl bor
  • Example 324 N-(3-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)benzyl)methanesulfonamide
  • the title compound was prepared in a method analogous to General Method H using 4-chloro- 7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 4-chloro-2- (methylthio)-5,5a,6,6a-tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidine and using 3- (methanesulfonamidomethyl)phenyl boronic acid instead of 3-carbamoylphenylboronic acid.
  • (2S,3R)-2-methylazetidin-3-ol hydrochloride salt was used instead of (2S)-2- methylazetidine (R)-camphorsulfonic acid salt.
  • Example 325 2-methyl-5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]oxazole
  • the title compound was prepared in a method analogous to General Method A using 2-methyl- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole and (S)-4-chloro-2-(2-methylazetidin-1- yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro- 6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 326 3-methyl-5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]isoxazole
  • the title compound was prepared in a method analogous to General Method A using 3-methyl- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole and (S)-4-chloro-2-(2-methylazetidin- 1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4- dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 327 3-methyl-5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]isothiazole
  • the title compound was prepared in a method analogous to General Method A using 3-methyl- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isothiazole and (S)-4-chloro-2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 328 tert-butyl N-[[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]carbamate
  • the title compound was prepared in a method analogous to General Method A using [3-[(tert- butoxycarbonylamino)methyl]phenyl]boronic acid and (S)-4-chloro-2-(2-methylazetidin-1-yl)- 6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7- dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 329 [3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]phenyl]methanamine
  • the title compound was prepared in a method analogous to General Method I, using tert-butyl N-[[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]phenyl]methyl]carbamate instead of tert-butyl (S)-4-(4-(2-(2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)piperazine-1-carboxylate.
  • Example 330 N-methyl-1-[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]methanamine
  • tert-butyl N-[[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]carbamate (76 mg, 0.193 mmol) in dimethylformamide (2 mL) under a dry nitrogen atmosphere was added 60% sodium hydride in mineral oil (12 mg, 0.29 mmol), and the reaction mixture was allowed to stir at room temperature for 30 minutes.
  • methyl iodide (0.024 mL, 0.38 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. It was diluted with ethyl acetate and washed with water and saturated sodium chloride. It was dried over anhydrous sodium sulfate, filtered, and concentrated. It was purified by flash column chromatography (ethyl acetate-hexanes) to yield tert-butyl (S)-methyl(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzyl)carbamate.
  • the title compound was prepared by General Method I using tert-butyl (S)-methyl(3-(2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzyl)carbamate instead of tert-butyl (S)-4-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)phenyl)piperazine-1-carboxylate.
  • Example 331 2-[(2S)-2-methylazetidin-1-yl]-4-phenyl-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method B using 2-chloro-4- phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 2-chloro-4-(pyridin-3-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidine.
  • Example 332 9-[(2S)-2-methylazetidin-1-yl]-7-phenyl-8,10-diazatricyclo[4.4.0.02,4]deca- 1(10),6,8-triene
  • the title compound was prepared in a method analogous to General Method H using phenyl boronic acid instead of (3-carbamoylphenyl)boronic acid.
  • Example 333 (5aR,6aR)-2-((S)-2-methylazetidin-1-yl)-4-phenyl-5,5a,6,6a- tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidine
  • Example 334 (5aS,6aS)-2-((S)-2-methylazetidin-1-yl)-4-phenyl-5,5a,6,6a- tetrahydrocyclopropa[4,5]cyclopenta[1,2-d]pyrimidine Isomers were separated by SFC (35% EtOH in CO 2 , CELL-2, 100 x 4.6 mm, 3 mL/min)
  • Example 335 2-[(2S)-2-methylazetidin-1-yl]-4-phenyl-spiro[5,7- dihydrocyclopenta[d]pyrimidine-6,1'-cyclopropane] The title compound was prepared in a method analogous to General Method H using
  • Example 336 7-methyl-2-[(2S)-2-methylazetidin-1-yl]-4-phenyl-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method H using methyl 3- methyl-2-oxocyclopentane-1-carboxylate and phenyl boronic acid instead of methyl 2- oxobicyclo[3.1.0]hexane-3-carboxylate and (3-carbamoylphenyl)boronic acid, respectively.
  • Example 337 6-methyl-2-[(2S)-2-methylazetidin-1-yl]-4-phenyl-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method H using methyl 4- methyl-2-oxocyclopentane-1-carboxylate and phenyl boronic acid instead of methyl 2- oxobicyclo[3.1.0]hexane-3-carboxylate and (3-carbamoylphenyl)boronic acid, respectively.
  • Example 338 2-[(2S)-2-methylazetidin-1-yl]-4-phenyl-spiro[5,6- dihydrocyclopenta[d]pyrimidine-7,1'-cyclopropane]
  • the title compound was prepared in a method analogous to General Method H using methyl 4- oxospiro[2.4]heptane-5-carboxylate and phenyl boronic acid instead of methyl 2- oxobicyclo[3.1.0]hexane-3-carboxylate and (3-carbamoylphenyl)boronic acid, respectively.
  • Example 339 5-methyl-2-[(2S)-2-methylazetidin-1-yl]-4-phenyl-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method H using methyl 2- methyl-5-oxocyclopentane-1-carboxylate and phenyl boronic acid instead of methyl 2- oxobicyclo[3.1.0]hexane-3-carboxylate and (3-carbamoylphenyl)boronic acid, respectively.
  • Example 340 5-methyl-2-[(2S)-2-methylazetidin-1-yl]-4-phenyl-5,6,7,8- tetrahydroquinazoline
  • the title compound was prepared in a method analogous to General Method H using methyl 2- methyl-6-oxocyclohexane-1-carboxylate and phenyl boronic acid instead of methyl 2- oxobicyclo[3.1.0]hexane-3-carboxylate and (3-carbamoylphenyl)boronic acid, respectively.
  • Example 341 2-[(2S)-2-methylazetidin-1-yl]-4-(3-methylimidazol-4-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method E using tributyl-(3- methylimidazol-4-yl)stannane instead of 2-tributylstannylimidazo[5,1-b]thiazole-7-carboxylate.
  • Example 342 5-methyl-2-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]thiazole
  • the title compound was prepared in a method analogous to General Method E using tributyl-(5- methylthiazol-2-yl)stannane instead of 2-tributylstannylimidazo[5,1-b]thiazole-7-carboxylate
  • Example 343 2-[(2S)-2-methylazetidin-1-yl]-4-pyridazin-4-yl-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method E using tributyl(pyridazin-4-yl)stannane instead of 2-tributylstannylimidazo[5,1-b]thiazole-7- carboxylate.
  • Example 344 2-[(2S)-2-methylazetidin-1-yl]-4-pyrazin-2-yl-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method E using tributyl(pyrazin-2-yl)stannane instead of 2-tributylstannylimidazo[5,1-b]thiazole-7-carboxylate.
  • Example 345 2-[(2S)-2-methylazetidin-1-yl]-4-[3-(1-piperidylmethyl)phenyl]-6,7-dihydro- 5H-cyclopenta[d]pyrimidine
  • the title compound was prepared by General Method O.
  • Example 346 N,N-dimethyl-1-[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]methanamine
  • the title compound was prepared in a method analogous to General Method O using 2.0M dimethylamine in tetrahydrofuran instead of piperidine.
  • Example 347 4-[3-(azetidin-1-ylmethyl)phenyl]-2-[(2S)-2-methylazetidin-1-yl]-6,7- dihydro-5H-cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method O using equimolar azetidine hydrochloride and triethylamine instead of piperidine.
  • Example 348 2-[(2S)-2-methylazetidin-1-yl]-4-[3-(pyrrolidin-1-ylmethyl)phenyl]-6,7- dihydro-5H-cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method O using pyrrolidine instead of piperidine.
  • Example 349 4-[[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]morpholine
  • the title compound was prepared in a method analogous to General Method O using morpholine instead of piperidine.
  • Example 350 1-[[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]azetidin-3-ol
  • the title compound was prepared in a method analogous to General Method O using equimolar 3-hydroxyazetidine hydrochloride and triethylamine instead of piperidine.
  • Example 351 5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzofuran-7-sulfonamide
  • the title compound was prepared in a method analagous to General Method D using 5-bromo- 2,3-dihydrobenzofuran-7-sulfonamide instead of 2-bromoimidazo[5,1-b]thiazole-7-carboxylate, followed by General Method E, using 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H- cyclopenta[d]pyrimidine instead of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine, followed by General Method M
  • Example 352 [3-[2-[(2S,3R)-3-fluoro-2-methyl-azetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]methanamine
  • the title compound was prepared in a method analogous to General Method A using [3-[(tert- butoxycarbonylamino)methyl]phenyl]boronic acid instead of 3-pyridylboronic acid, followed by General Method B, using (2S,3R)-3-fluoro-2-methyl-azetidine instead of (2S)-2- methylazetidine, followed by General Method I.
  • Example 353 [3-[2-[(2S,3R)-3-fluoro-2-methyl-azetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]methanamine
  • the title compound was prepared in a method analogous to General Method A using [3-[(tert- butoxycarbonylamino)methyl]phenyl]boronic acid instead of 3-pyridylboronic acid, followed by General Method B, using (2S,3R)-2-methylazetidin-3-ol instead of (2S)-2-methylazetidine, followed by General Method I.
  • Example 354 2-[(2S)-2-methylazetidin-1-yl]-4-(4-methylsulfonylphenyl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A using 4-chloro-2- [(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine and (4- methylsulfonylphenyl)boronic acid instead of 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 355 N-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]acetamide
  • the title compound was prepared in a method analogous to General Method A using 4-chloro-2- [(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine and (4- acetamidophenyl)boronic acid instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 356 N-(2-hydroxyethyl)-2-methyl-4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl]benzamide
  • the title compound was prepared in a method analogous to General Method A using 4-chloro-2- [(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine and (4-methoxycarbonyl- 3-methyl-phenyl)boronic acid instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively, followed by General Method C and General Method G using 2-aminoethanol instead of ammonia.
  • Example 357 N,N,2-trimethyl-4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]benzamide
  • the title compound was prepared in a method analogous to General Method A using 4-chloro-2- [(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine and (4-methoxycarbonyl- 3-methyl-phenyl)boronic acid instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively, followed by General Method C and General Method G using dimethylamine instead of ammonia.
  • Example 358 ethyl N-[[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]carbamate
  • To a solution of [4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]phenyl]methanamine (27 mg, 0.092 mmol) in dichloromethane (0.6 mL) was added triethylamine (0.026 mL, 0.18 mmol) and ethyl chloroformate (11 mg, 0.1 mmol), and the reaction mixture was allowed to stir at ambient temperature for 16 hours.
  • Example 359 ethyl N-[[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]carbamate
  • To a solution of [4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]phenyl]methanamine (27 mg, 0.092 mmol) in dichloromethane (0.6 mL) was added triethylamine (0.026 mL, 0.18 mmol) and ethyl chloroformate (11 mg, 0.1 mmol), and the reaction mixture was allowed to stir at ambient temperature for 16 hours.
  • Example 360 N-[[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]benzamide
  • the title compound was made in a method analogous to ethyl N-[[4-[2-[(2S)-2-methylazetidin- 1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]carbamate using benzoic anhydride instead of acetic anhydride.
  • Example 361 N-[[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]methanesulfonamide
  • the title compound was prepared in a method analogous to General Method K using [4-[2- [(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]phenyl]methanamine and mesyl chloride instead of (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)aniline and 1-methylimidazole-4-sulfonyl chloride, respectively.
  • Example 362 N-(2-hydroxyethyl)-2-methyl-4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl]benzamide
  • the title compound was prepared in a method analogous to General Method G using glyoxylic acid and [4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]phenyl]methanamine instead of 2-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid and ammonia, respectively.
  • Example 363 (2S,3R)-1-[4-[5-(aminomethyl)-2-thienyl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl]-2-methyl-azetidin-3-ol
  • the title compound was prepared in a method analogous to General Method A, using 5-[(tert- butoxycarbonylamino)methyl]-2-thienyl]boronic acid and 4-chloro-2-[(2S)-2-methylazetidin-1- yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro- 6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by General Methods B, using (2S,3R)-2-methylazetidin-3-ol instead of (2S)-2-methylazetidine, followed by General Method I.
  • Example 364 6-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]-2H-isoquinolin-1-one
  • the title compound was prepared in a method analogous to General Method A, using 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-isoquinolin-1-one and 4-chloro-2-[(2S)-2- methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 365 1-[[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]azetidin-3-ol
  • the title compound was prepared in a method analogous to General Method O using equimolar 3-hydroxyazetidine hydrochloride and triethylamine instead of piperidine and (4- formylphenyl)boronic acid instead of (3-formylphenyl)boronic acid.
  • Example 366 4-[4-(azetidin-1-ylmethyl)phenyl]-2-[(2S)-2-methylazetidin-1-yl]-6,7- dihydro-5H-cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method O using equimolar azetidine hydrochloride and triethylamine instead of piperidine and (4-formylphenyl)boronic acid instead of (3-formylphenyl)boronic acid.
  • Example 367 4-[[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]methyl]morpholine
  • the title compound was prepared in a method analogous to General Method O using morpholine instead of piperidine and (4-formylphenyl)boronic acid instead of (3-formylphenyl)boronic acid.
  • Example 368 N,N-dimethyl-1-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]methanamine
  • the title compound was prepared in a method analogous to General Method O using dimethylamine instead of piperidine and (4-formylphenyl)boronic acid instead of (3- formylphenyl)boronic acid.
  • Example 369 2-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl]phenyl]propan-2-ol
  • the title compound was prepared in a method analogous to General Method A, using [4-(1- hydroxy-1-methyl-ethyl)phenyl]boronic acid and 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7- dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7- dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 370 [2-fluoro-4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]methanol
  • the title compound was prepared in a method analogous to General Method A, using [3-fluoro- 4-(hydroxymethyl)phenyl]boronic acid and 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7- dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7- dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 371 (2S,3R)-1-[4-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl]-2-methyl-azetidin-3-ol
  • the title compound was prepared in a method analogous to General Method A using (2S,3R)-1- (4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-yl benzoate and [4- (1-hydroxy-1-methyl-ethyl)phenyl]boronic acid instead of 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively, followed by General Method C.
  • Example 372 (2S,3R)-1-[4-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl]-2-methyl-azetidin-3-ol
  • the title compound was prepared in a method analogous to General Method A using (2S,3R)-1- (4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-yl benzoate and [[3- fluoro-4-(hydroxymethyl)phenyl]boronic acid instead of 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively, followed by General Method C.
  • Example 373 6-[2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-2H-isoquinolin-1-one
  • the title compound was prepared in a method analogous to General Method A using (2S,3R)-1- (4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-yl benzoate and 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-isoquinolin-1-one instead of 2,4-dichloro-6,7- dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively, followed by General Method C.
  • Example 374 [4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]phenyl]methanol
  • the title compound was prepared in a method analogous to General Method A, using [4- (hydroxymethyl)phenyl]boronic acid and 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro- 5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 375 [5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]-2-thienyl]methanol
  • the title compound was prepared in a method analogous to General Method A, using [5- (hydroxymethyl)-2-thienyl]boronic acid and 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7- dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7- dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 376 2-[5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl]-2-thienyl]propan-2-ol
  • the title compound was prepared in a method analogous to General Method A, using 2-[5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl]propan-2-ol and 4-chloro-2-[(2S)-2- methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 377 N-[[5-[2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-2-thienyl]methyl]methanesulfonamide
  • the title compound was prepared in a method analogous to General Method K using (2S,3R)-1- [4-[5-(aminomethyl)-2-thienyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl]-2-methyl- azetidin-3-ol and mesyl chloride instead of (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)aniline and 1-methylimidazole-4-sulfonyl chloride, respectively.
  • Example 378 6-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]isoquinolin-1-amine
  • the title compound was prepared in a method analogous to General Method F, using 6- bromoisoquinolin-1-amine instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 379 6-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]-1,2,3,4-tetrahydroisoquinoline
  • the title compound was prepared in a method analogous to General Method A using tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate and 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3- pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by General Method I.
  • Example 380 6-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]isoquinolin-3-ol
  • 6-bromoisoquinolin-3-ol 200 mg, 0.89 mmol
  • imidazole 365 mg, 5.36 mmol
  • dimethylformamide 5 mL
  • chloro(triisopropyl)silane 688 mg, 3.57 mmol
  • Example 381 6-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]isoquinoline-1,3-diol
  • the title compound was prepared in a method analogous to General Method F, using 6- bromoisoquinoline-1,3-diol instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 382 8-fluoro-6-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-2H-isoquinolin-1-one
  • the title compound was prepared in a method analogous to General Method F, using 6-bromo-8- fluoro-2H-isoquinolin-1-one instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 383 7-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]-3H-quinazolin-4-one
  • the title compound was prepared in a method analogous to General Method A using 7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-quinazolin-4-one and 4-chloro-2-[(2S)-2- methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 384 2-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]-5H-thieno[3,2-c]pyridin-4-one
  • the title compound was prepared in a method analogous to General Method D using 2-bromo- 5H-thieno[3,2-c]pyridin-4-one instead of ethyl 2-bromoimidazo[5,1-b]thiazole-7-carboxylate, followed by General Method E.
  • Example 385 (2S,3R)-1-[4-(1-amino-6-isoquinolyl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl]-2-methyl-azetidin-3-ol
  • the title compound was prepared in a method analogous to General Method A using 6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-amine and (2S,3R)-1-(4-chloro-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-yl benzoate instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by General Method C.
  • Example 386 7-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]-3H-quinazolin-4-one
  • the title compound was prepared in a method analogous to General Method F, using 6-bromo-3- methyl-2H-isoquinolin-1-one instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 387 2-methyl-7-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-3H-quinazolin-4-one
  • the title compound was prepared in a method analogous to General Method F, using 7-bromo-2- methyl-3H-quinazolin-4-one instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 388 6-[2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]isoquinolin-3-ol
  • the title compound was prepared in a method analogous to General Method A using triisopropyl-[[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-isoquinolyl]oxy]silane instead of 3-pyridylboronic acid, followed by General Method B, using using (2S,3R)-2-methylazetidin- 3-ol instead of (2S)-2-methylazetidine.
  • Example 389 2-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]-1H-benzimidazole
  • the title compound was prepared according to General Method P.
  • Example 390 5-fluoro-1-methyl-2-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]benzimidazole
  • the title compound was prepared in a method analogous to General Method P using 4-fluoro-N- methyl-2-nitro-aniline instead of 2-nitroaniline.
  • Example 391 1-methyl-2-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]benzimidazole
  • the title compound was prepared in a method analogous to General Method P using N-methyl- 2-nitro-aniline instead of 2-nitroaniline.
  • Example 392 2-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]-6H-thieno[2,3-c]pyridin-7-one
  • the title compound was prepared in a method analogous to General Method D using 2-bromo- 6H-thieno[2,3-c]pyridin-7-one instead of ethyl 2-bromoimidazo[5,1-b]thiazole-7-carboxylate followed by General Method E.
  • Example 393 2-[(2S)-2-methylazetidin-1-yl]-4-pyrimidin-4-yl-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method E using tributyl(pyrimidin-4-yl)stannane instead of ethyl 2-tributylstannylimidazo[5,1-b]thiazole-7- carboxylate.
  • Example 394 2-[(2S)-2-methylazetidin-1-yl]-4-(1-methylimidazol-2-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method E using tributyl-(1- methylimidazol-2-yl)stannane instead of ethyl 2-tributylstannylimidazo[5,1-b]thiazole-7- carboxylate.
  • Example 395 3-methyl-2-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]benzimidazole-5-carboxylic acid
  • the title compound was prepared in a method analogous to General Method P using methyl 3- (methylamino)-4-nitro-benzoate instead of 2-nitroaniline, followed by General Method C.
  • Example 397 (S)-3-hydroxy-3-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)thietane 1,1-dioxide
  • the title intermediate was prepared in a method analogous to General Method F, using 3-(3- bromophenyl)-1,1-dioxo-thietan-3-ol instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 398 4-(2-(-1-methyl-7-azabicyclo[2.2.1]heptan-7-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method B using 1-methyl- 7-azabicyclo[2.2.1]heptane and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzamide instead of (S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 399 (S)-2-(2-methylazetidin-1-yl)-4-(3-(methylsulfonyl)phenyl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A, using (3- methylsulfonylphenyl)boronic acid and 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro- 5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 400 (S)-2-(2-methylazetidin-1-yl)-4-(3-(methylsulfinyl)phenyl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A, using (3- methylsulfinylphenyl)boronic acid and 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 401 (S)-4-(6-(2-methylazetidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-4- yl)benzamide
  • the title compound was prepared in a method analogous to 4-[5-[(2S)-2-methylazetidin-1-yl]- 1H-pyrazolo[4,3-d]pyrimidin-7-yl]benzamide, using 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine instead of 5,7-dichloro-1H-pyrazolo[4,3-d]pyrimidine.
  • Example 402 4-(2-(4-azaspiro[2.4]heptan-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzamide
  • the title compound was prepared in a method analogous to General Method B using 4- azaspiro[2.4]heptane hemioxalate and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzamide instead of (S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 403 (S)-4-(2-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method B using (S)-2- methylpyrrolidine and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide instead of (S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 404 (R)-4-(2-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method B using (R)-2- methylpyrrolidine and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide instead of (S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 405 4-(2-(azetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide
  • azetidine hydrochloride 85 mg, 0.91 mmol
  • cuprous iodide 0.17 g, 0.91 mmol
  • cesium carbonate 0.44 g, 1.4 mmol
  • DMF 1.5 mL
  • 4- (2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide (0.12 g, 0.45 mmol), 3,4,7,8- tetramethyl-1,10-phenanthroline (0.21 g, 0.91 mmol), and an additional volume of DMF (0.5 mL).
  • Example 406 rac-methyl (1R,2R)-5'-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-2-carboxylate (assigned as non-polar distereomer) and
  • Example 407 rac-methyl (1R,2S)-5'-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-2-carboxylate (assigned as polar distereomer)
  • Example 408 rac-(1R,2R)-5'-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-2-carboxylic acid (assigned as non-polar distereomer)
  • the title compound was prepared in a method analogous to General Method C using rac-methyl (1R,2R)-5'-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2'- oxospiro[cyclopropane-1,3'-indoline]-2-carboxylate instead of methyl (S)-3-(3-(2-(2- methylazetidin-1-yl)-6,7-dihydro-5H
  • Example 409 rac-(1R,2S)-5'-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-2-carboxylic acid (assigned as polar distereomer)
  • the title compound was prepared in a method analogous to General Method C using rac-methyl (1R,2S)-5'-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2'- oxospiro[cyclopropane-1,3'-indoline]-2-carboxylate instead of methyl (S)-3-(3-(2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-
  • Example 410 rac-(1R,2R)-5'-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-2-carbonitrile (assigned as non-polar diastereomer)
  • Example 411 rac-(1R,2S)-5'-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-2-carbonitrile (assigned as polar diastereomer)
  • the title compound was prepared in a method analogous to General Method F using 5'-bromo- 2'-oxo-spiro[cyclopropane-2,3'-indoline]-1-carbonitrile instead of 6-bromo-1,1-dioxo-1,2- benzothiazol-3-one.
  • Example 412 rac-(1R,2R)-5'-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-2-carboxamide (assigned as non-polar diastereomer)
  • Example 413 rac-(1R,2S)-5'-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-2-carboxamide (assigned as non-polar diastereomer)
  • a vial was charged with 5'-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5
  • Example 414 (1R,2R)-5'-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2-(1H-1,2,4-triazol-3-yl)spiro[cyclopropane-1,3'-indolin]-2'- one
  • Example 415 4-(2-(2-((methylthio)methyl)azetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method B using 2- (methylsulfanylmethyl)azetidine and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzamide instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 416 4-(2-(2-azaspiro[3.3]heptan-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzamide
  • the title compound was prepared in a method analogous to General Method B using 2- azaspiro[3.3]heptane and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 417 4-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method B using 2-oxa-6- azaspiro[3.3]heptane and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 418 4-(2-(2-oxopyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzamide
  • the title compound was prepared in a method analogous to General Method N using pyrrolidin- 2-one instead 2,3-dihydro-1H-imidazo[1,2-b]pyrazole.
  • Example 419 (S)-4-(2-(2-methyl-5-oxopyrrolidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method N using (5S)-5- methylpyrrolidin-2-one instead 2,3-dihydro-1H-imidazo[1,2-b]pyrazole.
  • Example 420 (S)-3-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)phenyl)-2H-thiete 1,1-dioxide
  • 3-(3-bromophenyl)-1,1-dioxo-thietan-3-ol (0.92 g, 3.3 mmol) in dichloromethane (15 mL) was treated successively with triethylamine (1.4 mL, 10 mmol) and then dropwise with methanesulfonyl chloride (0.77 mL, 10 mmol).
  • Example 421 (S)-3-(3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)phenyl)thietane 1,1-dioxide
  • a solution of 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thietane 1,1-dioxide prepared via the first step of General Method F on the substrate 3-(3-bromophenyl)thietane 1,1- dioxide) (0.40 g, 1.3 mmol) in ethanol (15 mL) was degassed before the introduction of 10 % palladium on carbon (wetted with ca.
  • the title compound was prepared from 3-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]thietane 1,1-dioxide and 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidine via the second step of General Method F.
  • Example 422 (S)-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-1,3-dihydrobenzo[c]thiophene 2,2-dioxide
  • the title compound was prepared in a method analogous to General Method F using by 5- bromo-1,3-dihydro-2-benzothiophene 2,2-dioxide instead of 6-bromo-1,1-dioxo-1,2- benzothiazol-3-one.
  • Example 423 (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)-1-naphthamide
  • the title compound was prepared in a method analogous to General Method F using 3-bromo-1- naphthamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 424 (S)-7-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)isoquinoline-1,3(2H,4H)-dione
  • the title compound was prepared in a method analogous to General Method F using 7-bromo- 4H-isoquinoline-1,3-dione instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 425 6-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]-1H-quinazoline-2,4-dione
  • the title compound was prepared in a method analogous to General Method F using 6-bromo- 1H-quinazoline-2,4-dione instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 426 7-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]-1H-quinazoline-2,4-dione
  • the title compound was prepared in a method analogous to General Method F using 7-bromo- 1H-quinazoline-2,4-dione instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 427 6-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]-2H-phthalazin-1-one
  • the title compound was prepared in a method analogous to General Method F using 6-bromo- 2H-phthalazin-1-one instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 428 3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylic acid
  • the title compound was prepared in a method analogous to General Method F using 3-bromo- 1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylic acid instead of 6-bromo-1,1-dioxo-1,2- benzothiazol-3-one.
  • Example 429 6-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]-2,3-dihydrophthalazine-1,4-dione
  • the title compound was prepared in a method analogous to General Method F using 6-bromo- 2,3-dihydrophthalazine-1,4-dione instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 430 4-[2-(1-azaspiro[3.3]heptan-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]benzamide
  • the title compound was prepared in a method analogous to General Method B using 1- azaspiro[3.3]heptane and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 431 4-[2-[(2S)-2-benzyl-3-hydroxy-azetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]benzamide
  • the title compound was prepared in a method analogous to General Method B using (2S)-2- benzylazetidin-3-ol and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 432 5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]-1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylic acid
  • the title compound was prepared in a method analogous to General Method F using 5-bromo- 1,1a,6,6a-tetrahydrocyclopropa[a]indene-1-carboxylic acid instead of 6-bromo-1,1-dioxo-1,2- benzothiazol-3-one.
  • Example 433 6-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]-1-oxo-2H-isoquinoline-4-sulfonamide
  • the title compound was prepared in a method analogous to General Method F using 6-bromo-1- oxo-2H-isoquinoline-4-sulfonamide instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 434 4-[2-(7-oxa-1-azaspiro[3.4]octan-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]benzamide
  • the title compound was prepared in a method analogous to General Method B using 7-oxa-1- azaspiro[3.4]octane and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 435 (1R,3R)-2,2-dimethyl-3-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)cyclopropane-1-carboxylic acid
  • the title compound was prepared in a method analogous to General Method F using (1R,3R)-3- (3-bromophenyl)-2,2-dimethyl-cyclopropanecarboxylic acid instead of 6-bromo-1,1-dioxo-1,2- benzothiazol-3-one.
  • Example 436 4-[2-[(2R)-2-(1-hydroxy-1-methyl-ethyl)azetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]benzamide
  • the title compound was prepared in a method analogous to General Method B using 2-[(2R)- azetidin-2-yl]propan-2-ol and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzamide instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 437 4-[2-[(2S)-3-fluoro-2-isobutyl-azetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]benzamide
  • the title compound was prepared in a method analogous to General Method B using (2S)-3- fluoro-2-isobutyl-azetidine and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzamide instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 438 4-[2-[(2R)-2-[(1R)-1-benzyloxyethyl]-3-hydroxy-azetidin-1-yl]-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl]benzamide
  • the title compound was prepared in a method analogous to General Method B using (2R)-2- [(1R)-1-benzyloxyethyl]azetidin-3-ol and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)benzamide instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidine, respectively.
  • Example 439 3-[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl]phenyl]cyclobutanecarboxylic acid
  • the title compound was prepared in a method analogous to General Method F using 3-(3- bromophenyl)cyclobutanecarboxylic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 440 (1R,3s)-3-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)cyclobutane-1-carboxylic acid
  • Example 441 (1S,3r)-3-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)cyclobutane-1-carboxylic acid
  • Isomers were separated by SFC (25% EtOH in CO 2 , CHIRALPAK AD-H, 100 x 4.6 mm, 3 mL/min).
  • Example 442 (2R)-1-[4-(4-carbamoylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- yl]azetidine-2-carboxylic acid
  • the title compound was prepared in a method analogous to General Method B using (2R)- azetidine-2-carboxylic acid and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzamide instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively.
  • Example 443 (1S,2S)-2-[3-chloro-5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]cyclopropanecarboxylic acid
  • the title compound was prepared in a method analogous to General Method F using (1S,2S)-2- (3-bromo-5-chloro-phenyl)cyclopropanecarboxylic acid instead of 6-bromo-1,1-dioxo-1,2- benzothiazol-3-one.
  • Example 444 4-(6,6-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-5,6,7,8- tetrahydroquinazolin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Method B using (2S,3R)-2- methylazetidin-3-ol and 4-(2-chloro-6,6-difluoro-5,6,7,8-tetrahydroquinazolin-4-yl)benzamide instead of (2S)-2-methylazetidine and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzamide, respectively.
  • Example 445 3-(2-((S)-2-methylazetidin-1-yl)-4b,5,5a,6- tetrahydrocyclopropa[3,4]cyclopenta[1,2-d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in a method analogous to General Methods A and B, using 2,4-dichloro-4b,5,5a,6-tetrahydrocyclopropa[3,4]cyclopenta[1,2-d]pyrimidine instead of 2,4- dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine.
  • Example 446 2-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]thieno[3,2-c]pyridin-4-amine
  • 2-bromothieno[3,2-c]pyridin-4-amine 500 mg, 2.18 mmol
  • triethylamine 1.52 mL, 10.9 mmol
  • N,N-dimethylpyridin-4-amine 53 mg, 0.44 mmol
  • tert-butoxycarbonyl tert-butyl carbonate 1.9 g, 8.7 mmol
  • Example 447 2-methyl-6-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]isoquinolin-1-one
  • the title compound was prepared in a method analogous to General Method F using 6-bromo-2- methyl-isoquinolin-1-one instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 448 (2S,3R)-1-[4-(3-amino-6-isoquinolyl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl]-2-methyl-azetidin-3-ol tert-butyl N-(6-bromo-3-isoquinolyl)-N-tert-butoxycarbonyl-carbamate was prepared in a method analogous to tert-butyl N-(2-bromothieno[3,2-c]pyridin-4-yl)-N-tert-butoxycarbonyl- carbamate using 6-bromo-3-aminoisoquinoline instead of 2-bromothieno[3,2-c]pyridin-4-amine.
  • Example 450 2-[2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-6H-thieno[2,3-c]pyridin-7-one
  • the title compound was prepared in a method analogous to General Method E using 2- tributylstannyl-6H-thieno[2,3-c]pyridin-7-one and (2S,3R)-1-(4-chloro-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-yl benzoate instead of ethyl 2- tributylstannylimidazo[5,1-b]thiazole-7-carboxylate and (S)-4-chloro-2-
  • Example 451 (S)-3-hydroxy-3-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)thietane 1,1-dioxide
  • the title compound was prepared in a method analogous to General Method F, using 3-(4- bromophenyl)-1,1-dioxo-thietan-3-ol instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 452 3-methyl-6-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d] pyrimidin-4-yl]-1H-benzimidazol-2-one
  • the title compound was prepared in a method analogous to General Method A using 3-methyl- 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzimidazol-2-one 3-pyridylboronic acid.
  • Example 453 4-[2-(difluoromethoxy)-4-pyridyl]-2-[(2S)-2-methylazetidin-1-yl]-6,7- dihydro-5H-cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A 2- (difluoromethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine instead of 3- pyridylboronic acid.
  • Example 454 trans-2-[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]cyclopropanecarbonitrile
  • the title compound was prepared in a method analogous to General Method F using trans-2-(3- bromophenyl)cyclopropanecarbonitrile instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one.
  • Example 455 1-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl]phenyl]cyclopropanecarboxylic acid
  • the title compound was prepared in a method analogous to General Method F using 1-(4- bromophenyl)cyclopropanecarboxylic acid instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3- one.
  • Example 456 trans-2-[3-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]cyclopropanecarboxamide
  • trans-2-[3-[2-[rel-(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]phenyl]cyclopropanecarbonitrile (52.6 mg, 0.16 mmol, 1 equiv.), ethanol (2 mL), and water (1 mL).
  • Parkins-Ghaffer catalyst (hydrido(dimethylphosphinousacid-kP)[hydrogenbis(dimethylphosphinito-kP)]platinum(II), 3.4 mg, 7.9 ⁇ mol, 5 mol%).
  • the vial was sealed and heated to 90°C for three hours.
  • the reaction mixture was cooled to room temperature, concentrated, and subjected to HPLC (0.1% TFA in MeCN-0.1% TFA in H 2 O) to give the title compound.
  • Example 457 4-[2-[(2R)-2-(methanesulfonamidomethyl)azetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]benzamide
  • the title compound was formed in a method analogous to General Method B using N-[[(2R)- azetidin-2-yl]methyl]methanesulfonamide and 4-(2-chloro-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide instead of (2S)-2-methylazetidine and 2-chloro-4- (pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively.
  • Example 458 4-(2-(2-cyanoazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzamide
  • the title compound was formed in a method analogous to General Method B using azetidine-2- carbonitrile hemioxalate and 4-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzamide and instead of (2S)-2-methylazetidine and 2-chloro-4-(pyridin-3-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidine, respectively.
  • Example 459 [5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl]-2-thienyl]methanamine
  • the title compound was prepared in a method analogous to General Method A, using [5-[(tert- butoxycarbonylamino)methyl]-2-thienyl]boronic acid and 4-chloro-2-[(2S)-2-methylazetidin-1- yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4-dichloro- 6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by General Methods B and I.
  • Example 460 N-[[5-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl]-2-thienyl]methyl]methanesulfonamide
  • the title compound was prepared in a method analogous to General Method K using [5-[2- [(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]-2- thienyl]methanamine and mesyl chloride instead of (S)-3-(2-(2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1-methylimidazole-4-sulfonyl chloride, respectively.
  • Example 461 (S)-4-(1-(azetidin-3-yl)-1H-1,2,3-triazol-4-yl)-2-(2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidine
  • 2-[(2S)-2-methylazetidin-1-yl]-4-vinyl-6,7-dihydro-5H- cyclopenta[d]pyrimidine 310 mg, 1.43 mmol
  • potassium carbonate 127 mg, 1.43 mmol
  • 1-diazo-1-dimethoxyphosphoryl-propan-2-one 0.278 mL, 1.85 mmol
  • the title compound was prepared in a method analogous to General Method I using tert-butyl 3- [4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]triazol-1- yl]azetidine-1-carboxylate instead of tert-butyl (S)-4-(4-(2-(2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)phenyl)piperazine-1-carboxylate.
  • Example 462 N-(3-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)benzyl)-N-methylmethanesulfonamide N-(3-(7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzyl)methanesulfonamide was prepared in a method analogous to General Method A using 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3- (methanesulfonamidomethyl)phenyl boronic acid instead of 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrim
  • reaction mixture was stirred at room temperature for 90 min after which hexamethyldisilazane (21 mL, 100 mmol) and 1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.8 g, 20 mmol) were added successively.
  • the mixture as stirred for 18 hr at room temperature, and the reaction mixture was concentrated.
  • the solids were taken up as a suspension in ethyl acetate/5 % aqueous hydrochloric acid, collected by suction filtration, washed with water and ethyl acetate, and dried under vacuum to provide N-(6-bromo-4-oxo-1H-quinazolin-2-yl)carbamate.
  • Example 464 (3-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)phenyl)(imino)(methyl)- ⁇ 6 -sulfanone
  • the title compound was prepared in a method analogous to General Method A using 4-chloro- 7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and imino(methyl)(3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-l6-sulfanone instead of 2,4-dichloro-6,7- dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively, followed by General Method M, followed by General Method B using (2S,3
  • Example 465 N-(6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzofuran-3-yl)methanesulfonamide
  • the title compound was prepared in a method analogous to General Method K using (rac)-6- bromo-2,3-dihydrobenzofuran-3-amine and methanesulfonyl chloride instead of (S)-3-(2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1- methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4- chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro
  • Example 466 N-((R)-6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzofuran-3- yl)methanesulfonamide
  • the title compound was prepared in a method analogous to General Method K using (R)-6- bromo-2,3-dihydrobenzofuran-3-amine and methanesulfonyl chloride instead of (S)-3-(2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1- methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4- chloro-7,7-difluoro-2-(methylthio)-6,7-di
  • Example 467 N-((S)-6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzofuran-3- yl)methanesulfonamide
  • the title compound was prepared in a method analogous to General Method K using (S)-6- bromo-2,3-dihydrobenzofuran-3-amine and methanesulfonyl chloride instead of (S)-3-(2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1- methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4- chloro-7,7-difluoro-2-(methylthio)-6,7-di
  • Example 468 3-(4-(7,7-difluoro-2-((2S,3R)-3-fluoro-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)phenyl)oxetan-3-amine
  • the title compound was prepared in a method analogous to General Method A using 4-chloro- 7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and benzyl (3-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-yl)carbamate instead of 2,4-dichloro-6,7- dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively, followed by General Method M, followed by General Method B using (2S,
  • Example 469 3-(4-(7,7-difluoro-2-((2S,3S)-3-fluoro-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)oxetan-3-amine
  • the title compound was prepared in a method analogous to General Method A using 4-chloro- 7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and benzyl (3-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-yl)carbamate instead of 2,4-dichloro-6,7- dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively, followed by General Method M, followed by General Method B using (2S,
  • Example 470 (S)-3-(4-(2-(3,3-difluoro-2-methylazetidin-1-yl)-7,7-difluoro-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)oxetan-3-amine
  • the title compound was prepared in a method analogous to General Method A using 4-chloro- 7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and benzyl (3-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-yl)carbamate instead of 2,4-dichloro-6,7- dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively, followed by General Method M, followed by General Method B using (S)-3
  • Example 471 (R)-3-(4-(7,7-difluoro-2-(2-(fluoromethyl)azetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)oxetan-3-amine
  • the title compound was prepared in a method analogous to General Method A using 4-chloro- 7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and benzyl (3-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-yl)carbamate instead of 2,4-dichloro-6,7- dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively, followed by General Method M, followed by General Method B using (R)-2-(flu
  • Example 472 N-((S)-5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)methanesulfonamide
  • the title compound was prepared in a method analogous to General Method K using (S)-5- bromo-2,3-dihydro-1H-inden-1-amine and methanesulfonyl chloride instead of (S)-3-(2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1- methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4- chloro-7,7-difluoro-2-(methylthio)-6,7-d
  • Example 473 N-((R)-5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)methanesulfonamide
  • the title compound was prepared in a method analogous to General Method K using (R)-5- bromo-2,3-dihydro-1H-inden-1-amine and methanesulfonyl chloride instead of (S)-3-(2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1- methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4- chloro-7,7-difluoro-2-(methylthio)-6,7-d
  • Example 474 5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrospiro[indene-1,4'-oxazolidin]-2'-one
  • a vial was charged with (1-amino-5-bromo-indan-1-yl)methanol (500 mg, 2.07 mmol) and THF (15 mL).
  • Triphosgene (613 mg, 2.07 mmol) was added slowly. The resulting mixture was heated to 70 o C for 2 hrs. The mixture was allowed to cool to ambient temperature.
  • Example 475 (R)-5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrospiro[indene-1,4'-oxazolidin]-2'-one
  • Example 476 (S)-5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrospiro[indene-1,4'-oxazolidin]-2'-one
  • Isomers were separated by SFC (30% EtOH in CO 2 , CHIRALPAK AD-H, 100 x 4.6 mm, 3 mL/min).
  • Example 477 N-(6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-4-methoxy-2,3-dihydrobenzofuran-3- yl)methanesulfonamide
  • the title compound was prepared in a method analogous to General Method K using 6-bromo-4- methoxy-2,3-dihydrobenzofuran-3-amine and methanesulfonyl chloride instead of (S)-3-(2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1- methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4- chloro-7,7-difluoro-2-(methylthio)-6
  • Example 478 N-((S)-6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-methoxy-2,3-dihydrobenzofuran-3- yl)methanesulfonamide
  • Example 479 N-((R)-6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-methoxy-2,3-dihydrobenzofuran-3- yl)methanesulfonamide
  • Isomers were separated by SFC (30% MeOH in CO 2 , CHIRALPAK AZ-H, 100 x 4.6 mm, 3 mL/min).
  • Example 480 N-((R)-6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl-4,4-d2)- 6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzofuran-3- yl)methanesulfonamide
  • the title compound was prepared in a method analogous to General Method K using (R)-6- bromo-2,3-dihydrobenzofuran-3-amine and methanesulfonyl chloride instead of (S)-3-(2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1- methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4- chloro-7,7-difluoro-2-(methylthio)
  • Example 481 6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2H-spiro[benzofuran-3,4'-oxazolidin]-2'-one
  • ethyl 6-bromobenzofuran-3-carboxylate (1.00 g, 3.72 mmol
  • Mg turnings (497 mg, 20.4 mmol)
  • MeOH 40 mL
  • the title compound was prepared in a method analogous to General Method F using 6- bromospiro[2H-benzofuran-3,4'-oxazolidine]-2'-one and 4-chloro-7,7-difluoro-2-(methylthio)- 6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one and 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by General Method M, and General Method B, using (2S,3R)-2- methylazetidin-3-ol instead of (2S)-2-methylazetidine.
  • Example 482 (S)-6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-2H-spiro[benzofuran-3,4'-oxazolidin]-2'-one
  • Example 483 (R)-6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2H-spiro[benzofuran-3,4'-oxazolidin]-2'-one
  • Isomers were separated by SFC (25% EtOH in CO 2 , CHIRALPAK AD-H, 100 x 4.6 mm, 3 mL/min).
  • Example 484 N-((R)-6-(7,7-difluoro-2-((2R,3R)-2-(fluoromethyl)-3-hydroxyazetidin-1-yl)- 6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzofuran-3- yl)methanesulfonamide
  • the title compound was prepared in a method analogous to General Method K using (R)-6- bromo-2,3-dihydrobenzofuran-3-amine and methanesulfonyl chloride instead of (S)-3-(2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1- methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4- chloro-7,7-difluoro-2-(methylthio)
  • Example 485 (R)-5'-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2',3'-dihydrospiro[imidazolidine-4,1'-indene]- 2,5-dione
  • the title compound was prepared in a method analogous to General Method F using 4-chloro- 7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and (R)-5'-bromo-2',3'- dihydrospiro[imidazolidine-4,1'-indene]-2,5-dione instead of 4-chloro-2-[(2S)-2-methylazetidin- 1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrim
  • Example 486 (S)-5'-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2',3'-dihydrospiro[imidazolidine-4,1'-indene]- 2,5-dione
  • the title compound was prepared in a method analogous to General Method F using 4-chloro- 7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and (S)-5'-bromo-2',3'- dihydrospiro[imidazolidine-4,1'-indene]-2,5-dione instead of 4-chloro-2-[(2S)-2-methylazetidin- 1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrim
  • Example 487 N-((R)-7-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)isochroman-4-yl)methanesulfonamide
  • the title compound was prepared in a method analogous to General Method K using (R)-7- bromoisochroman-4-amine and methanesulfonyl chloride instead of (S)-3-(2-(2-methylazetidin- 1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1-methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4-chloro-7,7-difluoro-2- (methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 4-ch
  • Example 488 (5S)-5'-[7,7-difluoro-2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-3-methyl-spiro[imidazolidine-5,1'-indane]-2,4-dione
  • 5S -5'-bromospiro[imidazolidine-5,1'-indane]-2,4-dione
  • DMF 1.5 mL
  • iodomethane 51 mg, 0.36 mmol
  • Example 489 8-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine 1,1-dioxide
  • the mixture was allowed to cool to room temperature before the portion-wise addition of sodium sulfate decahydrate (0.52 g). At the end of the addition, the mixture was briefly sonicated and was then filtered through a fritted pad of Celite®. The filter cake was washed with ethyl acetate and tetrahydrofuran. The filtrate was concentrated under reduced pressure to provide 8-bromo- 2,3,4,5-tetrahydro-1,4-benzothiazepine.
  • Example 490 (R)-8-(7,7-difluoro-2-(2-(fluoromethyl)azetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine 1,1-dioxide
  • the title compound was prepared in a method analogous to General Method F using 4-chloro- 7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and tert-butyl 8-bromo- 3,5-dihydro-2H-1,4-benzothiazepine-4-carboxylate instead of 4-chloro-2-[(2S)-2- methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 6-bromo-1,1-dio
  • Example 491 3-amino-3-(4-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)thietane 1,1-dioxide
  • ethyl 2-(4-bromophenyl)acetate 49 g, 200 mmol
  • paraformaldehyde 18 g, 600 mmol
  • the mixture was stirred overnight at room temperature.
  • the reaction was quenched with water, and the mixture was extracted with diethyl ether and ethyl acetate.
  • the combined organic extracts were washed successively with 5 % aqueous lithium chloride solution and saturated aqueous sodium chloride solution; dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure.
  • Example 492 (S)-(3-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)(imino)(methyl)- ⁇ 6 -sulfanone
  • Example 493 (R)-(3-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)(imino)(methyl)- ⁇ 6 -sulfanone Isomers were separated by SFC (35% EtOH in CO 2 , CHIRALPAK IC-5 ⁇ m, 250 x 21 mm, 60 mL/min).
  • Example 494 (5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-2-methoxyphenyl)(imino)(methyl)- ⁇ 6 -sulfanone
  • the title compound was prepared according to General Method S, followed by General Method F using 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and tert- butyl ((5-bromo-2-methoxyphenyl)(methyl)(oxo)- ⁇ 6 -sulfaneylidene)carbamate instead of 4- chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 6-
  • Example 495 (S)-(5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-methoxyphenyl)(imino)(methyl)- ⁇ 6 -sulfanone
  • Example 496 (R)-(5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-methoxyphenyl)(imino)(methyl)- ⁇ 6 -sulfanone
  • Isomers were separated by SFC (45% EtOH in CO 2 , CHIRALPAK AD-H, 100 x 4.6 mm, 3 mL/min).
  • Example 497 6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2H-spiro[benzofuran-3,3'-morpholin]-5'-one
  • ethyl 3-amino-6-bromo-2,3-dihydrobenzofuran-3-carboxylate 1.0 g, 3.5 mmol
  • MeOH 10 mL
  • NaBH 4 264 mg, 7.0 mmol
  • Example 498 (R)-6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2H-spiro[benzofuran-3,3'-morpholin]-5'-one
  • Example 499 (S)-6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-2H-spiro[benzofuran-3,3'-morpholin]-5'-one
  • Isomers were separated by SFC (35% MeOH in CO 2 , CHIRALPAK AD-H, 250 x 21 mm, 60 mL/min).
  • Example 500 7-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine 1,1-dioxide
  • a flask was charged with 4-bromo-2-fluoro-benzenesulfonyl chloride (1.00 g, 3.66 mmol) and DCM (40 mL).
  • N(iPr)2Et (1.91 mL, 1.42 g, 11.0 mmoL) was added followed by ethanolamine (0.33 mL, 335 mg, 5.48 mmol). The mixture was allowed to stir at ambient temperature for 1 hr. The mixture was concentrated and subject to flash column chromatography (DCM—MeOH) to provide 4-bromo-2-fluoro-N-(2-hydroxyethyl)benzenesulfonamide. A flask was charged with 4-bromo-2-fluoro-N-(2-hydroxyethyl)benzenesulfonamide (1.04 g, 3.49 mmol) and DMSO (10 mL), followed by KOtBu (783 mg, 6.98 mmol).
  • Example 501 4-(2-(2-methylcyclobutyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzamide
  • 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine 77.3 mg, 0.5 mmol
  • 2-methylcyclobutanecarboxylic acid 57 mg, 0.5 mmol
  • AgNO3 17.0 mmol
  • K 2 S 2 O 8 (135 mg, 0.5 mmol
  • DCM (3 mL)
  • H 2 O 3 mL
  • the title compound was prepared in analogy to General Method A, using 4-chloro-2-(2- methylcyclobutyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and (4-carbamoylphenyl)boronic acid instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 502 4-(2-(1-methylcyclobutyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)benzamide
  • a vial was charged with 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (77.3 mg, 0.5 mmol), 2-methylcyclobutanecarboxylic acid (114 mg, 1.0 mmol), AgNO 3 (34 mg, 0.20 mmol), K2S2O8 (270 mg, 1.0 mmol), DCM (3 mL), and H 2 O (3 mL).
  • the mixture was allowed to stir at ambient temperature for 24 hr.
  • the mixture was extracted with DCM (3 x 5 mL).
  • the title compound was prepared in analogy to General Method A, using 44-chloro-2-(1- methylcyclobutyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and (4-carbamoylphenyl)boronic acid instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively.
  • Example 503 (2S,3R)-1-(4-(4-(3-aminooxetan-3-yl)-3-fluorophenyl)-7,7-difluoro-6,7- dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-ol
  • the title compound was prepared according to General Method T, and in analogy to General Method F using 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and benzyl (3-(4-bromo-2-fluorophenyl)oxetan-3-yl)carbamate instead of 4-chloro-2-[(2S)-2- methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 6-bromo-1,1-dioxo-1,2- benzothi
  • Example 504 3-(4-(2-((2S,4S)-2,4-dimethylazetidin-1-yl)-7,7-difluoro-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)oxetan-3-amine
  • the title compound was prepared in a method analogous to General Method A using 4-chloro- 7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine tert-butyl (3-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-yl)carbamate instead of 2,4-dichloro-6,7- dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively, followed by General Method M, followed by General Method B using (2S,
  • Example 505 (2S,3R)-1-(4-(4-(3-aminooxetan-3-yl)-3-methylphenyl)-7,7-difluoro-6,7- dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-ol
  • the title compound was prepared in analogy to General Method T, using 3-(4-bromo-2-methyl- phenyl)oxetan-3-amine instead of 3-(4-bromo-2-fluoro-phenyl)oxetan-3-amine, followed by General Method F using 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H- cyclopenta[d]pyrimidine and benzyl (3-(4-bromo-2-methylphenyl)oxetan-3-yl)carbamate instead of 4-chloro-2-[(2S)-2-methylazet
  • Example 506 (2S,3R)-1-(4-(6-(3-aminooxetan-3-yl)pyridin-3-yl)-7,7-difluoro-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-ol
  • the title compound was prepared in analogy to General Method T, using 3-(5-bromo-2- pyridyl)oxetan-3-amine instead of 3-(4-bromo-2-fluoro-phenyl)oxetan-3-amine, followed by General Method F using 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H- cyclopenta[d]pyrimidine and benzyl (3-(5-bromo-2-pyridyl))oxetan-3-yl)carbamate instead of 4- chloro-2-[(2S)-2-
  • Example 507 (S)-3-(5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)pyrazin-2-yl)oxetan-3-amine
  • the title compound was prepared in analogy to General Method E, using 3-(5-bromopyrazin-2- yl)oxetan-3-amine and (S)-2-(2-methylazetidin-1-yl)-4-(tributylstannyl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine instead of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine and ethyl 2-tributylstannylimidazo[5,1-b]thiazole-7-carboxylate, respectively.
  • Example 508 (3-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)phenyl)(methyl)(methylimino)- ⁇ 6 -sulfanone
  • Example 509 (2S,3R)-1-(7,7-difluoro-4-(3-(methylsulfonyl)phenyl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-ol
  • the title compounds were prepared in analogy to General Method F using (3- bromophenyl)(methyl)(methylimino)- ⁇ 6 -sulfanone and 4-chloro-7,7-difluoro-2-(methylthio)-6,7- dihydro-5H-cyclopenta[d]pyrimidine instead
  • Example 510 ((3-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)phenyl)imino)dimethyl- ⁇ 6 -sulfanone
  • the title compound was prepared in analogy to General Method F using ((3- bromophenyl)imino)dimethyl- ⁇ 6 -sulfanone and 4-chloro-7,7-difluoro-2-(methylthio)-6,7- dihydro-5H-cyclopenta[d]pyrimidine instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one and 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyr
  • Example 511 (3-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)phenyl)(ethyl)(imino)- ⁇ 6 -sulfanone
  • the title compound was prepared in analogy to General Method F using (3- chlorophenyl)(ethyl)(imino)- ⁇ 6 -sulfanone and 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro- 5H-cyclopenta[d]pyrimidine instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one and 4- chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by
  • Example 512 (2S,3R)-1-(7,7-difluoro-4-(4-(3-fluoroazetidin-3-yl)phenyl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-ol
  • the title compound was prepared in analogy to General Method F using tert-butyl 3-(4- bromophenyl)-3-fluoro-azetidine-1-carboxylate and 4-chloro-7,7-difluoro-2-(methylthio)-6,7- dihydro-5H-cyclopenta[d]pyrimidine instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one and 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by General Method
  • Example 514 (2S,3R)-1-(4-(4-(3-aminooxetan-3-yl)-3-(trifluoromethyl)phenyl)-7,7- difluoro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-ol
  • the title compound was prepared in analogy to General Method T, using 3-(4-bromo-2- (trifluoromethyl)phenyl)oxetan-3-amine instead of 3-(4-bromo-2-fluoro-phenyl)oxetan-3-amine, followed by General Method F, using 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H- cyclopenta[d]pyrimidine and benzyl (3-(4-bromo-2-(trifluoromethyl)phenyl)oxetan-3- yl)carbamate instead
  • Example 517 (2S,3R)-1-(4-(4-((S)-3-aminotetrahydrofuran-3-yl)phenyl)-7,7-difluoro-6,7- dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-ol
  • Example 518 (2S,3R)-1-(4-(4-((R)-3-aminotetrahydrofuran-3-yl)phenyl)-7,7-difluoro-6,7- dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-ol
  • Isomers were separated by SFC (20% EtOH in CO 2 , CHIRALPAK IG, 20 x 21 mm, 60 mL/min).
  • Example 519 (S)-6-(2-(3,3-difluoro-2-methylazetidin-1-yl)-7,7-difluoro-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-3,4-dihydro-2H-spiro[isoquinoline-1,3'-oxetane]
  • the title compound was prepared in analogy to General Method T, using 6-bromo-3,4-dihydro- 2H-spiro[isoquinoline-1,3'-oxetane] instead of 3-(4-bromo-2-fluoro-phenyl)oxetan-3-amine, followed by General Method F using 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H- cyclopenta[d]pyrimidine and benzyl 6-bromo-3,4-dihydro-2H-spiro[isoquino
  • Example 520 7-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2,3,4,5-tetrahydro-1H-3,5-methanobenzo[c]azepin-1-one
  • the title compound was prepared in analogy to General Method F using 7-bromo-2,3,4,5- tetrahydro-1H-3,5-methanobenzo[c]azepin-1-one and 4-chloro-7,7-difluoro-2-(methylthio)-6,7- dihydro-5H-cyclopenta[d]pyrimidine instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one and 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopen
  • Example 522 (S)-2-chloro-5-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzenesulfonamide
  • the title compound was prepared in analogy to General Method E, using 2-chloro-5-iodo- benzenesulfonamide and (S)-2-(2-methylazetidin-1-yl)-4-(tributylstannyl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine instead of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine and ethyl 2-tributylstannylimidazo[5,1-b]thiazole-7-carboxylate, respectively.
  • Example 523 N-((R)-6-(7,7-difluoro-2-((2S,3R)-3-fluoro-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzofuran-3- yl)methanesulfonamide
  • the title compound was prepared in analogy to General Method K using (R)-6-bromo-2,3- dihydrobenzofuran-3-amine and methanesulfonyl chloride instead of (S)-3-(2-(2-methylazetidin- 1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1-methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4-chloro-7,7-difluoro-2- (methylthio)-6,7-dihydro-5
  • Example 524 N-((R)-6-(7,7-difluoro-2-((2S,3S)-3-fluoro-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzofuran-3- yl)methanesulfonamide
  • the title compound was prepared in analogy to General Method K using (R)-6-bromo-2,3- dihydrobenzofuran-3-amine and methanesulfonyl chloride instead of (S)-3-(2-(2-methylazetidin- 1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1-methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4-chloro-7,7-difluoro-2- (methylthio)-6,7-dihydro-5
  • Example 525 N-(5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-7-fluoro-2,3-dihydro-1H-inden-1-yl)methanesulfonamide
  • the title compound was prepared according to General Method V, and in analogy to General Method K using 5-bromo-7-fluoro-2,3-dihydro-1H-inden-1-amine and methanesulfonyl chloride instead of (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1-methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4-chloro-7,7-difluoro-2-(methyl
  • Example 526 N-((S)-5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-7-fluoro-2,3-dihydro-1H-inden-1- yl)methanesulfonamide
  • Example 527 N-((R)-5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-7-fluoro-2,3-dihydro-1H-inden-1- yl)methanesulfonamide
  • Isomers were separated by SFC (35% MeOH in CO 2 , CHIRALPAK AD-H, 250 x 21 mm, 60 mL/min).
  • Example 528 N-((R)-6-(7,7-difluoro-2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzofuran-3-yl)methanesulfonamide
  • the title compound was prepared in analogy to General Method K using (R)-6-bromo-2,3- dihydrobenzofuran-3-amine and methanesulfonyl chloride instead of (S)-3-(2-(2-methylazetidin- 1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1-methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4-chloro-7,7-difluoro-2- (methylthio)-6,7-dihydro-5H-cyclopenta[d
  • Example 529 N-(6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-4-methoxy-2,3-dihydrobenzofuran-3- yl)methanesulfonamide
  • a flask was charged with 5-bromo-7-fluoro-indan-1-one (1.00 g, 4.37 mmol) and NaOMe (25% solution in MeOH, 5 mL). The mixture was heated to 50 o C for 1 hour.
  • Example 530 N-((R)-6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-methoxy-2,3-dihydrobenzofuran-3- yl)methanesulfonamide
  • Example 531 N-((S)-6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-methoxy-2,3-dihydrobenzofuran-3- yl)methanesulfonamide
  • Isomers were separated by SFC (35% EtOH in CO 2 , CHIRALPAK AD-H, 250 x 21 mm, 60 mL/min).
  • Example 532 (5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-2-(difluoromethoxy)phenyl)(imino)(methyl)- ⁇ 6 -sulfanone
  • the title compound was prepared in analogy to General Method S using (5-bromo-2- (difluoromethoxy)phenyl)(methyl)sulfane instead of (5-bromo-2- methoxyphenyl)(methyl)sulfane, followed by General Method F using 4-chloro-7,7-difluoro-2- (methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and tert-butyl ((5-bromo-2- (difluoromethoxy)phenyl)(methyl)(oxo)- ⁇ 6
  • Example 533 (S)-(5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-(difluoromethoxy)phenyl)(imino)(methyl)- ⁇ 6 - sulfanone
  • Example 534 (R)-(5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-(difluoromethoxy)phenyl)(imino)(methyl)- ⁇ 6 - sulfanone
  • Isomers were separated by SFC (25% MeOH in CO 2 , CHIRALPAK AD-H, 250 x 21 mm, 60 mL/min).
  • Example 535 (5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-3-fluoro-2-methoxyphenyl)(imino)(methyl)- ⁇ 6 -sulfanone
  • the title compound was prepared in analogy to General Method S using (5-bromo-3-fluoro-2- methoxyphenyl)(methyl)sulfane instead of (5-bromo-2-methoxyphenyl)(methyl)sulfane, followed by General Method F using 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H- cyclopenta[d]pyrimidine and tert-butyl ((5-bromo-3-fluoro-2-methoxyphenyl)(methyl)(oxo)- ⁇ 6 -
  • Example 536 (S)-(5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-fluoro-2-methoxyphenyl)(imino)(methyl)- ⁇ 6 - sulfanone
  • Example 537 (R)-(5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3-fluoro-2-methoxyphenyl)(imino)(methyl)- ⁇ 6 - sulfanone
  • Isomers were separated by SFC (30% MeOH in CO 2 , CHIRALPAK AD-H, 250 x 21 mm, 60 mL/min).
  • Example 538 cyclopropyl(5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-methoxyphenyl)(imino)- ⁇ 6 -sulfanone
  • a vial was charged with (5-bromo-2-methoxyphenyl)(cyclopropyl)(imino)- ⁇ 6 -sulfanone (250 mg, 0.86 mmol) and THF (2 mL).
  • KOtBu (1M in THF, 1.03 mL) was added and the mixture stirred at ambient temperature for 30 min.
  • Boc 2 O (376 mg, 1.72 mmol) was then added and the mixture was allowed to stir for 18 hours at ambient temperature.
  • H 2 O (5 mL) was added, and the mixture was extracted with EtOAc (3 x 5 mL). The combined organics were dried over Na 2 SO 4 , filtered, and concentrated. The residue was subject to flash column chromatography (hexanes— ethyl acetate) to give tert-butyl ((5-bromo-2-methoxyphenyl)(cyclopropyl)(oxo)- ⁇ 6 - sulfaneylidene)carbamate.
  • Example 539 (S)-cyclopropyl(5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)- 6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-methoxyphenyl)(imino)- ⁇ 6 -sulfanone
  • Example 540 (R)-cyclopropyl(5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1- yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-methoxyphenyl)(imino)- ⁇ 6 -sulfanone
  • Isomers were separated by SFC (40% EtOH in CO 2 , CHIRALPAK AD-H, 250 x 21 mm, 60 mL/min).
  • Example 541 (2-cyclopropoxy-5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1- yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)(imino)(methyl)- ⁇ 6 -sulfanone
  • the title compound was prepared in analogy to General Method S using (5-bromo-2- cyclopropoxyphenyl)(methyl)sulfane instead of (5-bromo-2-methoxyphenyl)(methyl)sulfane, followed by General Method F using 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H- cyclopenta[d]pyrimidine and tert-butyl ((5-bromo-2-cyclopropoxyphenyl)(methyl)(oxo)- ⁇ 6 - sulfaneylidene)c
  • Example 542 (S)-(2-cyclopropoxy-5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin- 1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)(imino)(methyl)- ⁇ 6 -sulfanone
  • Example 543 (R)-(2-cyclopropoxy-5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin- 1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)(imino)(methyl)- ⁇ 6 -sulfanone
  • Isomers were separated by SFC (30% EtOH in CO 2 , CHIRALPAK AD-H, 250 x 21 mm, 60 mL/min).
  • Example 544 N-((3R)-6-(2-(2-(difluoromethyl)azetidin-1-yl)-7,7-difluoro-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzofuran-3-yl)methanesulfonamide
  • the title compound was prepared in analogy to General Method K using (R)-6-bromo-2,3- dihydrobenzofuran-3-amine and methanesulfonyl chloride instead of (S)-3-(2-(2-methylazetidin- 1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1-methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4-chloro-7,7-difluoro-2- (methylthio)-6,7-dihydro-5H-cyclopent
  • Example 545 N-((R)-6-(2-((R)-2-(difluoromethyl)azetidin-1-yl)-7,7-difluoro-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzofuran-3-yl)methanesulfonamide
  • Example 546 N-((R)-6-(2-((S)-2-(difluoromethyl)azetidin-1-yl)-7,7-difluoro-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzofuran-3-yl)methanesulfonamide
  • Isomers were separated by SFC (30% EtOH in CO 2 , CHIRALPAK AD-H, 250 x 21 mm, 60 mL/min).
  • Example 547 N-(2-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5- yl)methanesulfonamide
  • the title compound was prepared in analogy to General Method K using 2-bromo-6,7,8,9- tetrahydro-5H-benzo[7]annulen-5-amine and methanesulfonyl chloride instead of (S)-3-(2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1- methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4- chloro-7,7-di
  • Example 548 5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrospiro[indene-1,3'-morpholin]-5'-one
  • the title compound was prepared according to General Method Y and in analogy to General Method F using 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 5-bromo-2,3-dihydrospiro[indene-1,3'-morpholin]-5'-one instead of 4-chloro-2-[(2S)-2- methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 6-bromo-1,1-dioxo-1,2-
  • Example 549 (S)-5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrospiro[indene-1,3'-morpholin]-5'-one
  • Example 550 (R)-5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrospiro[indene-1,3'-morpholin]-5'-one
  • Isomers were separated by SFC (30% EtOH in CO 2 , CHIRALPAK AD-H, 250 x 21 mm, 60 mL/min).
  • Example 551 7-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)spiro[chromane-4,4'-imidazolidine]-2',5'-dione
  • the title compound was prepared according to General Method X and in analogy to General Method F using 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 7-bromospiro[chromane-4,4'-imidazolidine]-2',5'-dione instead of 4-chloro-2-[(2S)-2- methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 6-bromo-1,1-dioxo-1,2-
  • Example 552 5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrospiro[indene-1,3'-[1,4]oxazepan]-5'-one
  • the title compound was prepared in analogy to General Method Y using 3-chloropropanoyl chloride instead of 2-chloroacetyl chloride, and omitting the second step, followed by General Method F using 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 5-bromo-2,3-dihydrospiro[indene-1,3'-[1,4]oxazepan]-5'-one instead of 4-chloro-2-[(2S)-2- methyla
  • Example 553 7-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)spiro[chromane-4,4'-oxazolidin]-2'-one
  • a vial was charged with 7-bromospiro[chromane-4,4'-imidazolidine]-2',5'-dione (400 mg, 1.35 mmol) and NaOH (2M aq., 4.7 mL, 9.42 mmol).
  • the mixture was heated to 100 o C for 3 days.
  • Example 554 7-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)spiro[isochromane-4,4'-oxazolidin]-2'-one 7'-bromospiro[imidazolidine-4,4'-isochromane]-2,5-dione was prepared according to General Method X, using 7-bromoisochroman-4-one instead of 7-bromochroman-4-one. (4-amino-7- bromoisochroman-4-yl)methanol was prepared therefrom, in analogy to Example 553.
  • Example 555 (R)-7-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[isochromane-4,4'-oxazolidin]-2'-one
  • Example 556 (S)-7-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)spiro[isochromane-4,4'-oxazolidin]-2'-one
  • Isomers were separated by SFC (30% MeOH in CO 2 , CHIRALPAK AD-H, 250 x 21 mm, 60 mL/min).
  • Example 557 6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one
  • the title compound was prepared in analogy to General Method Z, using 1-amino-5-bromo-2,3- dihydro-1H-inden-2-ol instead of (1-amino-5-bromo-indan-1-yl)methanol, followed by General Method F using 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 6-bromo-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one instead of 4-chloro-2
  • Example 558 6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-6'-methyl-2H-spiro[benzofuran-3,3'-morpholin]-5'-one
  • the title compound was prepared in analogy to General Method Y using 2-chloropropanoyl chloride and (3-amino-6-bromo-2,3-dihydrobenzofuran-3-yl)methanol instead of 2-chloroacetyl chloride and (1-amino-5-bromo-2,3-dihydro-1H-inden-1-yl)methanol, respectively, followed by General Method F using 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H- cyclopenta[d]pyrimidine and 6-bromo-6'-methyl
  • Example 559 (3S)-6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-6'-methyl-2H-spiro[benzofuran-3,3'-morpholin]- 5'-one
  • Example 560 (3R)-6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-6'-methyl-2H-spiro[benzofuran-3,3'-morpholin]- 5'-one
  • SFC 35% EtOH in CO 2 , CHIRALPAK AD-H, 250 x 21 mm, 60 mL/min).
  • Example 561 (S)-(5-(7,7-difluoro-2-((2S,3R)-3-fluoro-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-2-methoxyphenyl)(imino)(methyl)- ⁇ 6 -sulfanone
  • the title compound was prepared according to General Method S, using (S)-4-bromo-1- methoxy-2-(methylsulfinyl)benzene instead of (rac)-4-bromo-1-methoxy-2- (methylsulfinyl)benzene, followed by General Method F using 4-chloro-7,7-difluoro-2- (methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and tert-butyl (S)-((5-bromo-2- methoxyphenyl)(methyl)(oxo
  • Example 562 (S)-(5-(7,7-difluoro-2-((2S,3S)-3-fluoro-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-2-methoxyphenyl)(imino)(methyl)- ⁇ 6 -sulfanone
  • the title compound was prepared according to General Method S, using (S)-4-bromo-1- methoxy-2-(methylsulfinyl)benzene instead of (rac)-4-bromo-1-methoxy-2- (methylsulfinyl)benzene, followed by General Method F using 4-chloro-7,7-difluoro-2- (methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and tert-butyl (S)-((5-bromo-2- methoxyphenyl)(methyl)(oxo
  • Example 563 (S)-(5-(2-((S)-3,3-difluoro-2-methylazetidin-1-yl)-7,7-difluoro-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-2-methoxyphenyl)(imino)(methyl)- ⁇ 6 -sulfanone
  • the title compound was prepared according to General Method S, using (S)-4-bromo-1- methoxy-2-(methylsulfinyl)benzene instead of (rac)-4-bromo-1-methoxy-2- (methylsulfinyl)benzene, followed by General Method F using 4-chloro-7,7-difluoro-2- (methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and tert-butyl (S)-((5-bromo-2- methoxyphenyl)(methyl)(oxo)
  • Example 564 (5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-2-(trifluoromethoxy)phenyl)(imino)(methyl)- ⁇ 6 -sulfanone
  • the title compound was prepared in analogy to General Method S, using (5-bromo-2- (trifluoromethoxy)phenyl)(methyl)sulfane instead of (5-bromo-2- methoxyphenyl)(methyl)sulfane, followed by General Method F using 4-chloro-7,7-difluoro-2- (methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and tert-butyl ((5-bromo-2- (trifluoromethoxy)phenyl)(methyl)(oxo)- ⁇ 6 -
  • Example 565 6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-5',5'-dimethyl-2H-spiro[benzofuran-3,4'-oxazolidin]-2'-one
  • a vial was charged with ethyl 3-amino-6-bromo-2,3-dihydrobenzofuran-3-carboxylate (500 mg, 1.75 mmol) and THF (10 mL).
  • Example 566 (R)-6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-5',5'-dimethyl-2H-spiro[benzofuran-3,4'- oxazolidin]-2'-one
  • Example 567 (S)-6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-5',5'-dimethyl-2H-spiro[benzofuran-3,4'-oxazolidin]-2'- one Isomers were separated by SFC (35% EtOH in CO 2 , CHIRALPAK AD-H, 250 x 21 mm, 60 mL/min).
  • Example 568 3-(4-(7,7-difluoro-2-(2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)oxetan-3-amine
  • the title compound was prepared in analogy to General Method A using 4-chloro-7,7-difluoro- 2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and benzyl (3-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-yl)carbamate instead of 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively, followed by General Method M, followed by General Method B using 2-ethylazetidine instead of (2S)-2-methylaze
  • Example 569 (R)-3-(4-(7,7-difluoro-2-(2-(methoxymethyl)azetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)oxetan-3-amine
  • the title compound was prepared in analogy to General Method A using 4-chloro-7,7-difluoro- 2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and benzyl (3-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-yl)carbamate instead of 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively, followed by General Method M, followed by General Method B using (R)-2-(methoxy
  • Example 570 (S)-3-(4-(7,7-difluoro-2-(2-methylpyrrolidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)oxetan-3-amine
  • the title compound was prepared in analogy to General Method A using 4-chloro-7,7-difluoro- 2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and benzyl (3-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-yl)carbamate instead of 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively, followed by General Method M, followed by General Method B using (S)-2-methylpyrrolidine instead of (2S)-2
  • Example 571 3-(4-(2-(2-azabicyclo[3.1.0]hexan-2-yl)-7,7-difluoro-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)oxetan-3-amine
  • the title compound was prepared in analogy to General Method A using 4-chloro-7,7-difluoro- 2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and benzyl (3-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-yl)carbamate instead of 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively, followed by General Method M, followed by General Method B using 2-azabicyclo[3.1.0]hexane instead
  • Example 572 3-(4-(2-(2-cyclobutylazetidin-1-yl)-7,7-difluoro-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)oxetan-3-amine
  • the title compound was prepared in analogy to General Method A using 4-chloro-7,7-difluoro- 2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and benzyl (3-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-yl)carbamate instead of 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively, followed by General Method M, followed by General Method B using 2-cyclobutylazetidine instead of (2S)-2-
  • Example 573 3-(4-(2-(2-(3,3-difluorocyclobutyl)azetidin-1-yl)-7,7-difluoro-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)oxetan-3-amine
  • the title compound was prepared in analogy to General Method A using 4-chloro-7,7-difluoro- 2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and benzyl (3-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-yl)carbamate instead of 2,4-dichloro-6,7-dihydro-5H- cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively, followed by General Method M, followed by General Method B using 2-(3,3-
  • Example 574 N-(2-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-5,6-dihydro-4H-cyclopenta[b]thiophen-4- yl)methanesulfonamide
  • the title compound was prepared in analogy to General Method W, using 2-bromo-5,6-dihydro- 4H-cyclopenta[b]thiophen-4-one instead of 5-bromo-7-methoxy-2,3-dihydro-1H-inden-1-one followed by General Method K, using 2-bromo-5,6-dihydro-4H-cyclopenta[b]thiophen-4-amine and methanesulfonyl chloride instead of (S)-3-(2-(2-methylazetidin-1-yl)-6,7-dihydro
  • Example 575 N-((R)-6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2,3-dimethylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzofuran-3- yl)methanesulfonamide
  • the title compound was prepared in analogy to General Method K using (R)-6-bromo-2,3- dihydrobenzofuran-3-amine and methanesulfonyl chloride instead of (S)-3-(2-(2-methylazetidin- 1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1-methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4-chloro-7,7-difluoro-2-(methylthio)- 6,7-dihydr
  • Example 576 5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2,3-dimethylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrospiro[indene-1,4'-oxazolidin]-2'-one
  • the title compound was prepared according to General Method Z, and in analogy to General Method F using 5-bromo-2,3-dihydrospiro[indene-1,4'-oxazolidin]-2'-one and 4-chloro-7,7- difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 6-bromo-1,1- dioxo-1,2-benzothiazol-3-one and 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7-di
  • Example 577 N-((R)-6-(7,7-difluoro-2-((R)-2-(trifluoromethyl)azetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzofuran-3-yl)methanesulfonamide
  • the title compound was prepared in analogy to General Method K using (R)-6-bromo-2,3- dihydrobenzofuran-3-amine and methanesulfonyl chloride instead of (S)-3-(2-(2-methylazetidin- 1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1-methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4-chloro-7,7-difluoro-2- (methylthio)-6,7-dihydro-5H-
  • Example 578 N-((S)-7-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)isochroman-4-yl)methanesulfonamide
  • the title compound was prepared in analogy to General Method K using (S)-7- bromoisochroman-4-amine and methanesulfonyl chloride instead of (S)-3-(2-(2-methylazetidin- 1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1-methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4-chloro-7,7-difluoro-2- (methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 4-chloro-2
  • Example 579 N-((R)-7-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)isochroman-4-yl)cyclopropanesulfonamide
  • the title compound was prepared in analogy to General Method K using (R)-7- bromoisochroman-4-amine and cyclopropylsulfonyl chloride instead of (S)-3-(2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1- methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4- chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of
  • Example 580 N-((R)-7-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)isochroman-4-yl)-1-fluoromethanesulfonamide
  • the title compound was prepared in analogy to General Method K using (R)-7- bromoisochroman-4-amine and fluoromethanesulfonyl chloride instead of (S)-3-(2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1- methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4- chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine
  • Example 581 N-((R)-7-(7,7-difluoro-2-((R)-2-(trifluoromethyl)azetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)isochroman-4-yl)methanesulfonamide
  • the title compound was prepared in analogy to General Method K using (R)-7- bromoisochroman-4-amine and methanesulfonyl chloride instead of (S)-3-(2-(2-methylazetidin- 1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1-methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4-chloro-7,7-difluoro-2- (methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 4-chloro
  • Example 582 N-((R)-7-(7,7-difluoro-2-((2S,3R)-3-fluoro-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)isochroman-4-yl)methanesulfonamide
  • the title compound was prepared in analogy to General Method K using (R)-7- bromoisochroman-4-amine and methanesulfonyl chloride instead of (S)-3-(2-(2-methylazetidin- 1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1-methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4-chloro-7,7-difluoro-2- (methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 4-chlor
  • Example 583 N-((R)-7-(7,7-difluoro-2-((2S,3S)-3-fluoro-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)isochroman-4-yl)methanesulfonamide
  • the title compound was prepared in analogy to General Method K using (R)-7- bromoisochroman-4-amine and methanesulfonyl chloride instead of (S)-3-(2-(2-methylazetidin- 1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1-methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4-chloro-7,7-difluoro-2- (methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 4-chlor
  • Example 584 N-((R)-7-(2-((S)-3,3-difluoro-2-methylazetidin-1-yl)-7,7-difluoro-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)isochroman-4-yl)methanesulfonamide
  • the title compound was prepared in analogy to General Method K using (R)-7- bromoisochroman-4-amine and methanesulfonyl chloride instead of (S)-3-(2-(2-methylazetidin- 1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1-methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4-chloro-7,7-difluoro-2- (methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 4-chloro
  • Example 586 3-[4-[7,7-difluoro-2-[(2R)-2-(trifluoromethyl)azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-2-methyl-phenyl]oxetan-3-amine
  • the title compound was prepared in analogy to General Method T, using 3-(4-bromo-2-methyl- phenyl)oxetan-3-amine hydrochloride instead 3-(4-bromo-2-fluoro-phenyl)oxetan-3-amine hydrochloride, followed by General Method F using benzyl (3-(4-bromo-2- methylphenyl)oxetan-3-yl)carbamate and 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H- cyclopenta[d]pyrimidine instead of 6-bromo-1,1-dioxo-1
  • Example 587 3-[4-[7,7-difluoro-2-[(2R)-2-(trifluoromethyl)azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]phenyl]tetrahydrofuran-3-amine
  • the title compound was prepared in analogy to General Method T, using 3-(4- bromophenyl)tetrahydrofuran-3-amine instead 3-(4-bromo-2-fluoro-phenyl)oxetan-3-amine hydrochloride, followed by General Method F using benzyl (3-(4-bromophenyl)tetrahydrofuran- 3-yl)carbamate and 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H- cyclopenta[d]pyrimidine instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one and
  • Example 588 (3R)-6-[7,7-difluoro-2-[(2R)-2-(trifluoromethyl)azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-N-(oxetan-3-yl)-2,3-dihydrobenzofuran-3-amine
  • (3R)-6-bromo-2,3-dihydrobenzofuran-3-amine hydrochloride (1.00 g, 3.99 mmol) and ZnCl2 (816 mg, 5.99 mmol) in MeOH (20 mL) was added 3-Oxetanone (863 mg, 12.0 mmol) dropwise over 1-2 min.
  • Example 589 3-[4-[7,7-difluoro-2-[(2R)-2-(trifluoromethyl)azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-2-fluoro-phenyl]oxetan-3-amine
  • the title compound was prepared using General Method T, followed by General Method F using benzyl (3-(4-bromo-2-fluorophenyl)oxetan-3-yl)carbamate and 4-chloro-7,7-difluoro-2- (methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 6-bromo-1,1-dioxo-1,2- benzothiazol-3-one and 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidine, respectively, followed
  • Example 591 8-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2-ethyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one
  • THF 2-aminobutan-2-ol
  • Di- tert-butyl decarbonate 982 mg, 4.50 mmol
  • Example 592 (S)-8-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-2-ethyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one
  • Example 593 (R)-8-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-ethyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)- Isomers were separated by SFC (35% MeOH in CO 2 , CHIRALPAK IG, 250 x 21 mm, 60 mL/min).
  • Example 595 (R)-8-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-(fluoromethyl)-3,4- dihydrobenzo[f][1,4]oxazepin-5(2H)-one
  • Example 596 (S)-8-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-2-(fluoromethyl)-3,4-dihydrobenzo[f][1,4]oxazepin- 5(2H)-one
  • Isomers were separated by SFC (40% MeOH in CO 2 , CHIRALPAK IG, 250 x 21 mm, 60 mL
  • Example 597 8-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2-(difluoromethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)- one
  • THF 2-amino-1,1-difluoro-propan-2-ol
  • di-tert-butyl decarbonate 982 mg, 4.50 mmol
  • reaction mixture was diluted with sat. aq. NaHCO3 (20 mL) and the layers separated. The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organics were dried over Na2SO4, filtered, and concentrated to give tert-butyl N-(3,3-difluoro-2- hydroxy-propyl)carbamate, which was used without further purification.
  • Example 598 6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide
  • the title compound was prepared in analogy to General Method F using 6-bromo-2,3-dihydro- 1,2-benzothiazole 1,1-dioxide and 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H- cyclopenta[d]pyrimidine instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one and 4-chloro-2- [(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by
  • Example 599 8-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-3,4-dihydropyrido[2,3-f][1,4]oxazepin-5(2H)-one
  • the title compound was prepared in analogy to General Method Q, using tert-butyl N-(2- hydroxyethyl)carbamate instead of tert-butyl (S)-(1-hydroxypropan-2-yl)carbamate, followed by General Method F using 8-bromo-3,4-dihydro-2H-pyrido[2,3-f][1,4]oxazepin-5-one and 4- chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of
  • Example 600 7-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one
  • the title compound was prepared in analogy to General Method A using 2-methyl-7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1-one and 4-chloro-7,7-difluoro-2- (methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3-pyridylboronic acid and 2,4- dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by General Method M, General Method B using (2S,3R)-2-
  • Example 602 (difluoromethyl)(imino)(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)- ⁇ 6 -sulfanone
  • the title compound was prepared in analogy to General Method E using (S)-2-(2- methylazetidin-1-yl)-4-(tributylstannyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of ethyl 2-tributylstannylimidazo[5,1-b]thiazole-7-carboxylate and (3-bromophenyl)- (difluoromethyl)-imino-oxo- ⁇ 6 -sulfane instead of (S)-4-chloro-2-(2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta
  • Example 603 (3-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)phenyl)(difluoromethyl)(imino)- ⁇ 6 -sulfanone
  • the title compound was prepared in analogy to General Method F using (3- bromophenyl)(difluoromethyl)(imino)- ⁇ 6 -sulfanone and 4-chloro-7,7-difluoro-2-(methylthio)- 6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one and 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine
  • Example 604 (S)-2-((7-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)acetonitrile
  • the title compound was prepared in analogy to General Method K using 7-bromo-1,2,3,4- tetrahydroisoquinoline and cyanomethanesulfonyl chloride instead of (S)-3-(2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1- methylimidazole-4-sulfonyl chloride, respectively, followed by General Method E using (S)-2- (2-methylazetidin-1-yl)-4-(tributylstannyl)-6,7-dihydro-5
  • Example 605 (S)-2-((7-(2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)ethan-1-ol
  • the title compound was prepared in analogy to General Method K using 7-bromo-1,2,3,4- tetrahydroisoquinoline and 2-hydroxyethane-1-sulfonyl instead of (S)-3-(2-(2-methylazetidin-1- yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1-methylimidazole-4-sulfonyl chloride, respectively, followed by General Method E using (S)-2-(2-methylazetidin-1-yl)-4- (tributylstannyl)-6,7-dihydro-5
  • Example 606 3-(3-(2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl)phenyl)isothiazolidine 1,1-dioxide
  • the title compound was prepared in analogy to General Method E using (S)-2-(2- methylazetidin-1-yl)-4-(tributylstannyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-(3- bromophenyl)isothiazolidine 1,1-dioxide, instead of ethyl 2-tributylstannylimidazo[5,1- b]thiazole-7-carboxylate.
  • Example 607 3-(4-(7,7-difluoro-2-((2S,3S)-3-fluoro-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)oxetan-3-amine
  • the title compound was prepared in a method analogous to General Method K using 6-bromo- 2,3-dihydro-1H-inden-1-amine and methanesulfonyl chloride instead of (S)-3-(2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1- methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4- chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of
  • Example 608 N-((R)-6-(7,7-difluoro-2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)methanesulfonamide
  • Example 609 N-((S)-6-(7,7-difluoro-2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)methanesulfonamide
  • Isomers were separated by SFC (30% MeOH in CO 2 , CHIRALPAK AD-H, 250 x 21 mm, 60 mL/min).
  • Example 610 N-(3-(2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzyl)cyclopropanesulfonamide
  • the title compound was prepared in analogy to General Method K using (3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)methanamine and cyclopropylsulfonyl chloride instead of (S)-3- (2-(2-methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1- methylimidazole-4-sulfonyl chloride, respectively, followed by General Method A using (2S,3R)-1-(4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-y
  • Example 611 (2S,3R)-1-(7,7-difluoro-4-(2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin- 7-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-ol
  • the title compound was prepared in analogy to General Method A using tert-butyl 7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate and 4-chloro- 7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3- pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed
  • Example 612 (2S,3R)-1-(7,7-difluoro-4-(1,2,3,4-tetrahydroisoquinolin-7-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-ol
  • the title compound was prepared in analogy to General Method O using tert-butyl 7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate and 4-chloro- 7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 3- pyridylboronic acid and 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, respectively, followed by General Method M, followed by General Method B using
  • Example 613 N-(5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzofuran-3-yl)methanesulfonamide
  • the title compound was prepared in analogy to General Method K using 5-bromo-2,3- dihydrobenzofuran-3-amine and methanesulfonyl chloride instead of (S)-3-(2-(2-methylazetidin- 1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1-methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F, followed by General Method M, followed by General Method B using (2S,3R)-2-methylazetidin-3-ol instead of (2S)-2-
  • Example 614 N-((R)-5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzofuran-3- yl)methanesulfonamide
  • Example 615 N-((S)-5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzofuran-3- yl)methanesulfonamide
  • Isomers were separated by SFC (20% MeOH in CO 2 , CHIRALPAK IA, 250 x 21 mm, 60 mL/min).
  • Example 616 3-(3-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)phenyl)isothiazolidine 1,1-dioxide
  • the title compound was prepared in a method analogous to General Method F using 4-chloro- 7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-(3- bromophenyl)isothiazolidine 1,1-dioxide instead of 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7- dihydro-5H-cyclopenta[d]pyrimidine and 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one, respectively, followed by General Method M, followed by using
  • Example 617 (R)-3-(3-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)isothiazolidine 1,1-dioxide
  • Example 618 (S)-3-(3-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenyl)isothiazolidine 1,1-dioxide
  • Isomers were separated by SFC (35% MeOH in CO 2 , CHIRALPAK ADH, 250 x 21 mm, 60 mL/min).
  • Example 619 (2S,3R)-1-(4-(3-(4H-1,2,4-triazol-4-yl)phenyl)-7,7-difluoro-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)-2-methylazetidin-3-ol
  • the title compound was prepared in a method analogous to General Method F using 4-chloro- 7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 4-(3-bromophenyl)- 4H-1,2,4-triazole instead of 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidine and 6-bromo-1,1-dioxo-1,2-benzothiazol-3-one , respectively, followed by General Method M, followed by General Method
  • Example 620 2-(3-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)benzyl)isothiazolidine 1,1-dioxide
  • the title compound was prepared in a method analogous to General Method O using 4-chloro- 7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 2-(3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)isothiazolidine 1,1-dioxide instead of 4-chloro-2- [(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 6-bromo-1,1-dio
  • Example 621 N-(6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)methanesulfonamide
  • the title compound was prepared in a method analogous to General Method K using 6-bromo- 2,3-dihydro-1H-inden-1-amine and methanesulfonyl chloride instead of (S)-3-(2-(2- methylazetidin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)aniline and 1- methylimidazole-4-sulfonyl chloride, respectively, followed by General Method F using 4- chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H
  • Example 622 N-((S)-6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)methanesulfonamide
  • Example 623 N-((R)-6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydro-1H-inden-1-yl)methanesulfonamide
  • Isomers were separated by SFC (20% MeOH in CO 2 , CHIRALPAK AD-H, 250 x 21 mm, 60 mL/min).
  • Example 624 N-((R)-6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzofuran-3-yl)ethanesulfonamide
  • the title compound was prepared in a method analogous to General Method AB using (R)-6- bromo-2,3-dihydrobenzofuran-3-amine instead of 6-bromo-1,1-dioxo-2,3- dihydrobenzothiophen-3-amine, followed by General Method F using 4-chloro-7,7-difluoro-2- (methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 4-chloro-2-[(2S)-2- methylazetidin-1-yl]-6,7-dihydro-5H
  • Example 625 N-((R)-6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzofuran-3- yl)cyclopropanesulfonamide
  • the title compound was prepared in a method analogous to General Method AB using (R)-6- bromo-2,3-dihydrobenzofuran-3-amine instead of 6-bromo-1,1-dioxo-2,3- dihydrobenzothiophen-3-amine, followed by General Method F using 4-chloro-7,7-difluoro-2- (methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 4-chloro-2-[(2S)-2- methylazetidin-1-yl]-6,7-dihydro
  • Example 626 N-((R)-6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzofuran-3-yl)benzenesulfonamide
  • the title compound was prepared in a method analogous to General Method AB using (R)-6- bromo-2,3-dihydrobenzofuran-3-amine instead of 6-bromo-1,1-dioxo-2,3- dihydrobenzothiophen-3-amine, followed by General Method F using 4-chloro-7,7-difluoro-2- (methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 4-chloro-2-[(2S)-2- methylazetidin-1-yl]-6,7-dihydro-5H
  • Example 627 1-cyano-N-((R)-6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)- 6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrobenzofuran-3- yl)methanesulfonamide
  • the title compound was prepared in a method analogous to General Method AB using (R)-6- bromo-2,3-dihydrobenzofuran-3-amine instead of 6-bromo-1,1-dioxo-2,3- dihydrobenzothiophen-3-amine, followed by General Method F using 4-chloro-7,7-difluoro-2- (methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 4-chloro-2-[(2S)-2- methylazetidin-1-yl]-6,7-
  • Example 628 2-(3-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)phenylsulfonimidoyl)acetonitrile
  • the title compound was prepared in a method analogous to General Method F using 4-chloro- 7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and tert-butyl ((3- bromophenyl)(cyanomethyl)(oxo)-l6-sulfaneylidene)carbamate instead of 4-chloro-2-[(2S)-2- methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 6-bromo-1,1-dioxo
  • Example 629 N-(5-(7,7-difluoro-2-((R)-2-(fluoromethyl)azetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-inden-1- yl)methanesulfonamide
  • the title compound was prepared in a method analogous to General Method W using 5-bromo- 3,3-dimethyl-2,3-dihydro-1H-inden-1-one instead of 5-bromo-7-methoxy-2,3-dihydro-1H- inden-1-one, followed by General Method K using methanesulfonyl chloride instead of 1- methylimidazole-4-sulfonyl chloride, followed by General Method F using 4-chloro-7,7- difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[
  • Example 630 N-(5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-inden-1- yl)methanesulfonamide
  • the title compound was prepared in a method analogous to General Method W using 5-bromo- 3,3-dimethyl-2,3-dihydro-1H-inden-1-one instead of 5-bromo-7-methoxy-2,3-dihydro-1H- inden-1-one, followed by General Method K using methanesulfonyl chloride instead of 1- methylimidazole-4-sulfonyl chloride, followed by General Method F using 4-chloro-7,7- difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopent
  • Example 631 N-((R)-5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-inden-1- yl)methanesulfonamide
  • Example 632 N-((S)-5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-inden-1- yl)methanesulfonamide
  • Isomers were separated by SFC (15% EtOH in CO 2 , CHIRALPAK OJ-H, 250 x 21 mm, 60 mL
  • Example 633 N-(5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-3,3-difluoro-2,3-dihydro-1H-inden-1- yl)methanesulfonamide
  • the title compound was prepared in a method analogous to General Method W using 5-bromo- 3,3-difluoro-2,3-dihydro-1H-inden-1-one instead of 5-bromo-7-methoxy-2,3-dihydro-1H-inden- 1-one, followed by General Method K using methanesulfonyl chloride instead of 1- methylimidazole-4-sulfonyl chloride, followed by General Method F using 4-chloro-7,7- difluoro-2-(methylthio)-6,7-dihydro-5H
  • Example 634 N-((S)-5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3,3-difluoro-2,3-dihydro-1H-inden-1- yl)methanesulfonamide
  • Example 635 N-((R)-5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-3,3-difluoro-2,3-dihydro-1H-inden-1- yl)methanesulfonamide
  • Isomers were separated by SFC (15% EtOH in CO 2 , CHIRALPAK OJ-H, 250 x 21 mm,
  • Example 636 5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrospiro[indene-1,2'-pyrrolidin]-5'-one
  • the title compound was prepared according to General Method AE, followed by General Method F using 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine instead of 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine, followed by General Method M, followed by General Method B using (2S,3R)-2- methylazetidin-3-ol instead of (2S)-2-methylazetidine.
  • Example 637 (R)-5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrospiro[indene-1,2'-pyrrolidin]-5'-one
  • Example 638 (S)-5-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-2,3-dihydrospiro[indene-1,2'-pyrrolidin]-5'-one
  • Isomers were separated by SFC (35% EtOH in CO 2 , CHIRALPAK AD-H, 250 x 21 mm, 60 mL/min).
  • Example 639 7-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)spiro[isochromane-4,2'-pyrrolidin]-5'-one
  • n-BuLi in hexanes 9.9 mL, 1.6M
  • a 0 °C slurry of methyltriphenylphosphonium bromide (4000 mg, 14.5 mmol) in THF (45 mL).
  • Example 640 (R)-7-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[isochromane-4,2'-pyrrolidin]-5'-one
  • Example 641 (S)-7-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)spiro[isochromane-4,2'-pyrrolidin]-5'-one
  • Isomers were separated by SFC (35% EtOH in CO 2 , CHIRALPAK AD-H, 250 x 21 mm, 60 mL/min).
  • Example 642 6-[7,7-difluoro-2-[(2S)-2-methylazetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinoline
  • the title compound was prepared in a method analogous to General Method A using 4-chloro- 7,7-difluoro-2-[(2S)-2-methylazetidin-1-yl]-5,6-dihydrocyclopenta[d]pyrimidine and tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid respectively, followed by General Method I.
  • Example 643 2-[7,7-difluoro-2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-6H-thieno[2,3-c]pyridin-7-one
  • the title compound was prepared in a method analogous to General Method D using 2-bromo- 6H-thieno[2,3-c]pyridin-7-one instead of ethyl 2-bromoimidazo[5,1-b]thiazole-7-carboxylate, followed by General Method E using [(2S,3R)-1-(4-chloro-7,7-difluoro-5,6- dihydrocyclopenta[d]pyrimidin-2-yl)-2-methyl-azetidin-3-yl] benzoate instead of (S)-4-chloro- 2-(2-methylazetidin-1-yl)-6,7-dihydro-5
  • Example 644 4-(1-cyclopropyltriazol-4-yl)-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method AA using azidocyclopropane instead of 3-azidooxetane.
  • Example 645 2-[4-[2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 4-yl]triazol-1-yl]ethanol
  • the title compound was prepared in a method analogous to General Method AA using 2- azidoethanol instead of 3-azidooxetane.
  • Example 646 (2S,3R)-1-[4-[4-(1-amino-3,3-difluoro-cyclobutyl)phenyl]-7,7-difluoro-5,6- dihydrocyclopenta[d]pyrimidin-2-yl]-2-methyl-azetidin-3-ol
  • the title compound was prepared in a method analogous to General Method A using [(2S,3R)-1- (4-chloro-7,7-difluoro-5,6-dihydrocyclopenta[d]pyrimidin-2-yl)-2-methyl-azetidin-3-yl] benzoate and tert-butyl N-[3,3-difluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]cyclobutyl]carbamate instead of 2,4-dichloro-6,7-dihydro-5H-
  • Example 647 (2S,3R)-1-[4-[1-(azetidin-3-yl)triazol-4-yl]-7,7-difluoro-5,6- dihydrocyclopenta[d]pyrimidin-2-yl]-2-methyl-azetidin-3-ol
  • the title compound was prepared in a method analogous to General Method P using [(2S,3R)-1- (4-chloro-7,7-difluoro-5,6-dihydrocyclopenta[d]pyrimidin-2-yl)-2-methyl-azetidin-3-yl] benzoate instead of 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H- cyclopenta[d]pyrimidine, omitting the last step to yield [(2S,3R)-1-(7,7-difluoro-4-formyl-5,6- dihydrocyclopen
  • Example 648 1-[4-[7,7-difluoro-2-[(2S)-2-methylazetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]phenyl]-3,3-difluoro-cyclobutanamine
  • the title compound was prepared in a method analogous to General Method A using 4-chloro- 7,7-difluoro-2-[(2S)-2-methylazetidin-1-yl]-5,6-dihydrocyclopenta[d]pyrimidine and tert-butyl N-[3,3-difluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl]carbamate instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid respectively, followed by
  • Example 649 (1R)-1-[4-[7,7-difluoro-2-[(2S)-2-methylazetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]phenyl]-2,2-difluoro-ethanamine
  • the title compound was prepared in a method analogous to General Method A using 4-chloro- 7,7-difluoro-2-[(2S)-2-methylazetidin-1-yl]-5,6-dihydrocyclopenta[d]pyrimidine and tert-butyl N-[(1R)-2,2-difluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamate instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid
  • Example 650 (1S)-1-[4-[7,7-difluoro-2-[(2S)-2-methylazetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]phenyl]-2,2-difluoro-ethanamine
  • the title compound was prepared in a method analogous to General Method A using 4-chloro- 7,7-difluoro-2-[(2S)-2-methylazetidin-1-yl]-5,6-dihydrocyclopenta[d]pyrimidine and tert-butyl N-[(1S)-2,2-difluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamate instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid
  • Example 651 (1R)-1-[4-[7,7-difluoro-2-[(2S)-2-methylazetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]phenyl]-2,2-difluoro-ethanamine
  • the title compound was prepared in a method analogous to General Method A using 4-chloro-2- [(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine and tert-butyl N-[(1R)- 2,2-difluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamate instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid respectively, followed by General Method
  • Example 652 (1S)-1-[4-[7,7-difluoro-2-[(2S)-2-methylazetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]phenyl]-2,2-difluoro-ethanamine
  • the title compound was prepared in a method analogous to General Method A using 4-chloro-2- [(2S)-2-methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine and tert-butyl N-[(1S)- 2,2-difluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamate instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid respectively, followed by General Method
  • Example 653 4-[1-(azetidin-3-yl)triazol-4-yl]-7,7-difluoro-2-[(2S)-2-methylazetidin-1-yl]- 5,6-dihydrocyclopenta[d]pyrimidine
  • 4-chloro-7,7-difluoro-2-[(2S)-2-methylazetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidine 100 mg, 0.39 mmol
  • copper(I) iodide 5.5 mg, 0.03 mmol
  • bis(triphenylphosphine)palladium(II) chloride 23 mg, 0.019 mmol
  • triethylamine 3 mL
  • ethynyl(trimethyl)silane 0.16 mL, 1.2 mmol
  • Example 654 7,7-difluoro-2-[(2S)-2-methylazetidin-1-yl]-4-[3-(triazol-1-yl)phenyl]-5,6- dihydrocyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A using 4-chloro- 7,7-difluoro-2-[(2S)-2-methylazetidin-1-yl]-5,6-dihydrocyclopenta[d]pyrimidine and [3-(triazol- 1-yl)phenyl]boronic acid instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid respectively.
  • Example 655 7,7-difluoro-2-[(2S)-2-methylazetidin-1-yl]-4-[4-(triazol-1-yl)phenyl]-5,6- dihydrocyclopenta[d]pyrimidine
  • the title compound was prepared in a method analogous to General Method A using 4-chloro- 7,7-difluoro-2-[(2S)-2-methylazetidin-1-yl]-5,6-dihydrocyclopenta[d]pyrimidine and [4-(triazol- 1-yl)phenyl]boronic acid instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid respectively.
  • Example 656 6-[7,7-difluoro-2-[(2S)-2-methylazetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-1,1-dioxo-2,3-dihydrobenzothiophen-3-amine
  • the title compound was prepared in a method analogous to General Method V using 6-bromo- 1,1-dioxo-benzothiophen-3-one instead of 5-bromo-7-fluoro-2,3-dihydro-1H-inden-1-one, followed by General Method F using 4-chloro-7,7-difluoro-2-[(2S)-2-methylazetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidine and tert-butyl N-(6-bromo-1,1-dioxo-2,3- dihydrobenzothiophen-3-yl)carbamate instead of 4-ch
  • Example 657 (2S,3R)-1-[7,7-difluoro-4-(1,2,3,4-tetrahydroisoquinolin-6-yl)-5,6- dihydrocyclopenta[d]pyrimidin-2-yl]-2-methyl-azetidin-3-ol
  • the title compound was prepared in a method analogous to General Method A using 4-chloro- 7,7-difluoro-2-methylsulfanyl-5,6-dihydrocyclopenta[d]pyrimidine and tert-butyl 6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate instead of 2,4- dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid respectively, followed by General Method M, followed by General Method B using (2S,3R)-2-
  • Example 658 (2S,3R)-1-[4-(3-amino-1,1-dioxo-2,3-dihydrobenzothiophen-6-yl)-7,7- difluoro-5,6-dihydrocyclopenta[d]pyrimidin-2-yl]-2-methyl-azetidin-3-ol
  • the title compound was prepared in a method analogous to General Method V using 6-bromo- 1,1-dioxo-benzothiophen-3-one instead of 5-bromo-7-fluoro-2,3-dihydro-1H-inden-1-one, followed by General Method F using 4-chloro-7,7-difluoro-2-methylsulfanyl-5,6- dihydrocyclopenta[d]pyrimidine and tert-butyl N-(6-bromo-1,1-dioxo-2,3- dihydrobenzothiophen-3-yl)carbamate instead of 4-chloro
  • Example 659 (2S,3R)-1-[4-[4-[(1R)-1-amino-2,2-difluoro-ethyl]phenyl]-7,7-difluoro-5,6- dihydrocyclopenta[d]pyrimidin-2-yl]-2-methyl-azetidin-3-ol
  • the title compound was prepared in a method analogous to General Method A using 4-chloro- 7,7-difluoro-2-methylsulfanyl-5,6-dihydrocyclopenta[d]pyrimidine and tert-butyl N-[(1R)-2,2- difluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamate instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid respectively, followed
  • Example 660 (2R)-1-[4-[4-[(1R)-1-amino-2,2-difluoro-ethyl]phenyl]-7,7-difluoro-5,6- dihydrocyclopenta[d]pyrimidin-2-yl]azetidine-2-carbonitrile
  • the title compound was prepared in a method analogous to General Method A using 4-chloro- 7,7-difluoro-2-methylsulfanyl-5,6-dihydrocyclopenta[d]pyrimidine and tert-butyl N-[(1R)-2,2- difluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]carbamate instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid respectively, followed by General Method M, followed by
  • Example 661 6-[7,7-difluoro-2-[(2S)-2-methylazetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-1,1-dioxo-2,3-dihydrobenzothiophen-3-amine
  • the title compound was prepared in analogy to General Method S using 5-bromo-2,3- dihydrobenzothiophene instead of (5-bromo-2-methoxyphenyl)(methyl)sulfane, followed by General Method F using 4-chloro-7,7-difluoro-2-[(2S)-2-methylazetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidine and tert-butyl N-(6-bromo-1,1-dioxo-2,3- dihydrobenzothiophen-3-yl)carbamate instead of 4-chloro-2-[(2S)-2-methyl
  • Example 662 (2S,3R)-1-[4-[(3R)-3-amino-1,1-dioxo-2,3-dihydrobenzothiophen-6-yl]-7,7- difluoro-5,6-dihydrocyclopenta[d]pyrimidin-2-yl]-2-methyl-azetidin-3-ol
  • Example 663 (2S,3R)-1-[4-[(3S)-3-amino-1,1-dioxo-2,3-dihydrobenzothiophen-6-yl]-7,7- difluoro-5,6-dihydrocyclopenta[d]pyrimidin-2-yl]-2-methyl-azetidin-3-ol
  • Isomers were separated by SFC (30% EtOH in CO 2 , CHIRALPAK OJ-H, 250 x 21 mm, 60 mL/min).
  • Example 665 N-[6-[7,7-difluoro-2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-1,1-dioxo-2,3-dihydrobenzothiophen-3- yl]methanesulfonamide
  • the title compound was prepared in a method analogous to General Method F using 4-chloro- 7,7-difluoro-2-methylsulfanyl-5,6-dihydrocyclopenta[d]pyrimidine and N-(6-bromo-1,1-dioxo- 2,3-dihydrobenzothiophen-3-yl)methanesulfonamide instead of 4-chloro-2-[(2S)-2- methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine and 6-
  • Example 666 (2S,3R)-1-[7,7-difluoro-4-(1-imino-1-oxo-2,3-dihydrobenzothiophen-6-yl)- 5,6-dihydrocyclopenta[d]pyrimidin-2-yl]-2-methyl-azetidin-3-ol
  • the title compound was prepared in analogy to General Method S using 6-bromo-2,3- dihydrobenzothiophene instead of (5-bromo-2-methoxyphenyl)(methyl)sulfane, followed by General Method F using 4-chloro-7,7-difluoro-2-methylsulfanyl-5,6- dihydrocyclopenta[d]pyrimidine and tert-butyl N-(6-bromo-1,1-dioxo-2,3- dihydrobenzothiophen-3-yl)carbamate instead of 4-chloro-2-[(2S)-2-methylazetidin
  • Example 668 cyclopropyl-[3-[7,7-difluoro-2-[(2S)-2-methylazetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]phenyl]imino-methyl-oxo- ⁇ 6 -sulfane
  • 77-difluoro-2-[(2S)-2-methylazetidin-1-yl]-4-[3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl]-5,6-dihydrocyclopenta[d]pyrimidine 60 mg, 0.14 mmol
  • dimethylformamide 1.1 mL
  • cyclopropyl-imino-methyl-oxo- ⁇ 6 -sulfane 20 mg, 0.17 mmol
  • copper(II) acetate 2.6 mg, 0.014 mmol
  • Example 669 1-[3-[7,7-difluoro-2-[(2S)-2-methylazetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]phenyl]iminothiolane 1-oxide
  • the title compound was prepared in a method analogous to cyclopropyl-[3-[7,7-difluoro-2- [(2S)-2-methylazetidin-1-yl]-5,6-dihydrocyclopenta[d]pyrimidin-4-yl]phenyl]imino-methyl- oxo- ⁇ 6 -sulfane (Example 668) substituting 1-iminothiolane 1-oxide, copper(I) iodide, and methanol for cyclopropyl-imino-methyl-
  • Example 670 (2S,3R)-1-[7,7-difluoro-4-(1-imino-1-oxo-2,3-dihydrobenzothiophen-6-yl)- 5,6-dihydrocyclopenta[d]pyrimidin-2-yl]-2-methyl-azetidin-3-ol [1-[(3R)-6-bromo-2,3-dihydrobenzofuran-3-yl]triazol-4-yl]-trimethyl-silane was prepared in a method analogous to General Method AA using (3R)-3-azido-6-bromo-2,3-dihydrobenzofuran and ethynyl(trimethyl)silane instead of 3-azidooxetane and 4-ethynyl-2-[(2S)-2-methylazetidin- 1-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine respectively.
  • Example 671 (2S,3R)-1-[7,7-difluoro-4-[3-[(1-oxothiolan-1-ylidene)amino]phenyl]-5,6- dihydrocyclopenta[d]pyrimidin-2-yl]-2-methyl-azetidin-3-ol
  • the title compound was prepared in a method analogous to General Method AC using 1- iminothiolane 1-oxide instead of cyclopropyl-imino-methyl-oxo- ⁇ 6 -sulfane.
  • Example 672 (2S,3R)-1-[7,7-difluoro-4-[3-[(1-oxo-1,4-thiazinan-1-ylidene)amino]phenyl]- 5,6-dihydrocyclopenta[d]pyrimidin-2-yl]-2-methyl-azetidin-3-ol
  • the title compound was prepared in a method analogous to General Method AC using tert-butyl 1-imino-1-oxo-1,4-thiazinane-4-carboxylate instead of cyclopropyl-imino-methyl-oxo- ⁇ 6 - sulfane, followed by General Method I.
  • Example 673 (2S,3R)-1-[7,7-difluoro-4-[3-[(4-oxo-1,4-oxathian-4-ylidene)amino]phenyl]- 5,6-dihydrocyclopenta[d]pyrimidin-2-yl]-2-methyl-azetidin-3-ol
  • the title compound was prepared in a method analogous to General Method AC using 4-imino- 1,4-oxathiane 4-oxide instead of cyclopropyl-imino-methyl-oxo- ⁇ 6 -sulfane.
  • Example 674 N-[6-[7,7-difluoro-2-[(2S,3R)-3-fluoro-2-methyl-azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-1,1-dioxo-2,3-dihydrobenzothiophen-3- yl]methanesulfonamide
  • the title compound was prepared in a method analogous to General Method F using 4-chloro- 7,7-difluoro-2-methylsulfanyl-5,6-dihydrocyclopenta[d]pyrimidine and tert-butyl N-(6-bromo- 1,1-dioxo-2,3-dihydrobenzothiophen-3-yl)carbamate instead of 4-chloro-2-[(2S)-2- methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyr
  • Example 675 N-[6-[7,7-difluoro-2-[(2S,3R)-3-fluoro-2-methyl-azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-1,1-dioxo-2,3-dihydrobenzothiophen-3- yl]methanesulfonamide
  • the title compound was prepared in a method analogous to General Method F using 4-chloro- 7,7-difluoro-2-methylsulfanyl-5,6-dihydrocyclopenta[d]pyrimidine and tert-butyl N-(6-bromo- 1,1-dioxo-2,3-dihydrobenzothiophen-3-yl)carbamate instead of 4-chloro-2-[(2S)-2- methylazetidin-1-yl]-6,7-dihydro-5H-cyclopenta[d]pyr
  • Example 676 (5S)-5'-[7,7-difluoro-2-[(2R)-2-(fluoromethyl)azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-3-methyl-spiro[imidazolidine-5,1'-indane]-2,4-dione
  • the title compound was prepared in a method analogous to General Method F using 4-chloro- 7,7-difluoro-2-methylsulfanyl-5,6-dihydrocyclopenta[d]pyrimidine and (5S)-5'-bromo-3-methyl- spiro[imidazolidine-5,1'-indane]-2,4-dione instead of 4-chloro-2-[(2S)-2-methylazetidin-1-yl]- 6,7-dihydro-5H-cyclopenta[d]pyrimidine and 6-bromo-1,1-dioxo-1
  • Example 677 (2R,3R)-1-[4-[4-(3-aminooxetan-3-yl)phenyl]-7,7-difluoro-5,6- dihydrocyclopenta[d]pyrimidin-2-yl]-2-(fluoromethyl)azetidin-3-ol
  • the title compound was prepared in a method analogous to General Method A using 4-chloro- 7,7-difluoro-2-methylsulfanyl-5,6-dihydrocyclopenta[d]pyrimidine and benzyl N-[3-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxetan-3-yl]carbamate instead of 2,4-dichloro-6,7- dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid respectively, followed by General Method M, followed by General Method B using (2R
  • Example 678 3-[4-[2-[2-(difluoromethyl)azetidin-1-yl]-7,7-difluoro-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]phenyl]oxetan-3-amine
  • the title compound was prepared in a method analogous to General Method A using 4-chloro- 7,7-difluoro-2-methylsulfanyl-5,6-dihydrocyclopenta[d]pyrimidine and benzyl N-[3-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxetan-3-yl]carbamate instead of 2,4-dichloro-6,7- dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid respectively, followed by General Method M, followed by General Method B using 2-(difluoromethyl)azetidine hydroch
  • Example 679 N-[(3R)-6-[7,7-difluoro-2-[(2S,3R)-3-fluoro-2-methyl-azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-1,1-dioxo-2,3-dihydrobenzothiophen-3- yl]methanesulfonamide
  • Example 680 N-[(3S)-6-[7,7-difluoro-2-[(2S,3R)-3-fluoro-2-methyl-azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-1,1-dioxo-2,3-dihydrobenzothiophen-3- yl]methanesulfonamide
  • Isomers were separated by SFC (25% MeOH in CO 2 , CHIRALPAK AD-H, 250 x 21 mm
  • Example 681 N-[(3R)-6-[2-[(2S)-3,3-difluoro-2-methyl-azetidin-1-yl]-7,7-difluoro-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-1,1-dioxo-2,3-dihydrobenzothiophen-3- yl]methanesulfonamide
  • Example 682 N-[(3S)-6-[2-[(2S)-3,3-difluoro-2-methyl-azetidin-1-yl]-7,7-difluoro-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-1,1-dioxo-2,3-dihydrobenzothiophen-3- yl]methanesulfonamide
  • Isomers were separated by SFC (30% MeOH in CO 2 , CHIRALPAK AD-H, 250 x
  • Example 683 3-[4-[7,7-difluoro-2-[2-(trifluoromethyl)azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]phenyl]oxetan-3-amine
  • the title compound was prepared in a method analogous to General Method A using 4-chloro- 7,7-difluoro-2-methylsulfanyl-5,6-dihydrocyclopenta[d]pyrimidine and benzyl N-[3-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxetan-3-yl]carbamate instead of 2,4-dichloro-6,7- dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid respectively, followed by General Method M, followed by General Method B using 2-(trifluoromethyl)azet
  • Example 684 4-[3-[(amino-methyl-oxo- ⁇ 6 -sulfanylidene)amino]phenyl]-7,7-difluoro-2- [(2S)-2-methylazetidin-1-yl]-5,6-dihydrocyclopenta[d]pyrimidine
  • dichloro(triphenyl)-lambda5-phosphane 175 mg, 0.525 mmol
  • dry chloroform (1 mL)
  • triethylamine 0.1 mL, 0.72 mmol
  • Example 685 (5S)-5'-[7,7-difluoro-2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-3-ethyl-spiro[imidazolidine-5,1'-indane]-2,4-dione
  • the title compound was prepared in a method analogous to General Method AD using ethyl iodide instead of methyl iodide, followed by General Method F using 4-chloro-7,7-difluoro-2- methylsulfanyl-5,6-dihydrocyclopenta[d]pyrimidine instead of 4-chloro-2-[(2S)-2- methylazetidin-1-yl
  • Example 686 (5S)-5'-[7,7-difluoro-2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-3-(2-hydroxyethyl)spiro[imidazolidine-5,1'-indane]- 2,4-dione
  • Example 687 3-[4-[2-[(2R)-2-(difluoromethyl)azetidin-1-yl]-7,7-difluoro-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]phenyl]oxetan-3-amine
  • Example 688 3-[4-[2-[(2S)-2-(difluoromethyl)azetidin-1-yl]-7,7-difluoro-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]phenyl]oxetan-3-amine
  • Isomers were separated by SFC (20% MeOH in CO 2 , CHIRALPAK AD-H, 250 x 21 mm, 60 mL/min).
  • 6-bromo-3'-ethyl-spiro[2H-benzofuran-3,5'-imidazolidine]-2',4'-dione was prepared in a method analogous to General Method AD using 6-bromospiro[2H-benzofuran-3,5'-imidazolidine]-2',4'- dione and ethyl iodide instead of (5S)-5'-bromospiro[imidazolidine-5,1'-indane]-2,4-dione and methyl iodide respectively.
  • Example 690 6-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-1'-isopropyl-2H-spiro[benzofuran-3,4'-imidazolidine]-2',5'- dione
  • the title compound was prepared in analogy to General Method AD using 6-bromospiro[2H- benzofuran-3,5'-imidazolidine]-2',4'-dione and 2-iodopropane instead of (5S)-5'- bromospiro[imidazolidine-5,1'-indane]-2,4-dione and methyl iodide respectively, followed by General Method F using 4-chloro-7,7-difluoro-2-methylsulfanyl-5,6- dihydrocyclopenta[d]pyrimidine and 6-brom
  • Example 691 (R)-N'-(3-(7,7-difluoro-2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)methanesulfonimidamide
  • Example 692 (S)-N'-(3-(7,7-difluoro-2-((S)-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)methanesulfonimidamide
  • Isomers were separated by SFC (30% EtOH in CO 2 , CHIRALPAK AD-H, 250 x 21 mm, 60 mL/min).
  • Example 693 6-[7,7-difluoro-2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-3'-propyl-spiro[2H-benzofuran-3,5'-imidazolidine]- 2',4'-dione
  • the title compound was prepared in a method analogous to General Method AD using 6- bromospiro[2H-benzofuran-3,5'-imidazolidine]-2',4'-dione and 1-iodopropane instead of (5S)-5'- bromospiro[imidazolidine-5,1'-indane]-2,4-dione and methyl iodide respectively followed by General Method F using 4-chloro-7,7-difluoro-2-methylsulfanyl-5,6- dihydrocyclopenta[d]pyrimidine and
  • Example 694 6-[7,7-difluoro-2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-3'-(oxetan-3-yl)spiro[2H-benzofuran-3,5'- imidazolidine]-2',4'-dione
  • the title compound was prepared in a method analogous to General Method AD using 6- bromospiro[2H-benzofuran-3,5'-imidazolidine]-2',4'-dione and 3-iodooxetane instead of (5S)-5'- bromospiro[imidazolidine-5,1'-indane]-2,4-dione and methyl iodide respectively, followed by General Method F using 4-chloro-7,7-difluoro-2-methylsulfanyl-5,6- dihydrocyclopenta[
  • Example 695 6-[7,7-difluoro-2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-1'-methyl-spiro[2H-benzofuran-3,4'-imidazolidine]- 2'-one 6-bromo-1'-methyl-2H-spiro[benzofuran-3,4'-imidazolidine]-2',5'-dione was prepared in a method analogous to General Method AD using 6-bromospiro[2H-benzofuran-3,5'- imidazolidine]-2',4'-dione instead of (5S)-5'-bromospiro[imidazolidine-5,1'-indane]-2,4-dione.
  • Example 696 3-[4-[7,7-difluoro-2-[(2R)-2-(trifluoromethyl)azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]phenyl]oxetan-3-amine
  • the title compound was prepared in a method analogous to General Method A using 4-chloro- 7,7-difluoro-2-methylsulfanyl-5,6-dihydrocyclopenta[d]pyrimidine and benzyl N-[3-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxetan-3-yl]carbamate instead of 2,4-dichloro-6,7- dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid respectively, followed by General Method M, followed by General Method U, followed by General Method R.
  • Example 697 (3R)-6-[7,7-difluoro-2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-3'-ethyl-spiro[2H-benzofuran-3,5'-imidazolidine]- 2',4'-dione
  • Example 698 (3S)-6-[7,7-difluoro-2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-3'-ethyl-spiro[2H-benzofuran-3,5'-imidazolidine]- 2',4'-dione
  • Isomers were separated by SFC (20% MeOH in CO 2 , CHIRALPAK IG, 250 x 21 mm, 60 mL
  • Example 699 6-[7,7-difluoro-2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-3'-(2,2,2-trifluoroethyl)spiro[2H-benzofuran-3,5'- imidazolidine]-2',4'-dione
  • the title compound was prepared in a method analogous to General Method AD using 6- bromospiro[2H-benzofuran-3,5'-imidazolidine]-2',4'-dione and 1,1,1-trifluoro-2-iodo-ethane instead of (5S)-5'-bromospiro[imidazolidine-5,1'-indane]-2,4-dione and methyl iodide with heating to 60 °C for 72 hours instead of ambient temperature for 16 hours, followed by General Method F using 4-chloro
  • Example 700 6-[7,7-difluoro-2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-1'-(2-hydroxyethyl)spiro[2H-benzofuran-3,4'- imidazolidine]-2'-one 6-bromo-1'-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2H-spiro[benzofuran-3,4'-imidazolidine]- 2',5'-dione was prepared in a method analogous to General Method AD using 6-bromospiro[2H- benzofuran-3,5'-imidazolidine]-2',4'-dione and 2-bromoethoxy-tert-butyl-dimethyl-silane instead of (5S)-5'-bromospiro[imidazolidine-5,1'-
  • 6-bromo-1'-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2H-spiro[benzofuran-3,4'-imidazolidin]-2'- one was prepared in a method analogous to 6-bromo-1'-methyl-spiro[2H-benzofuran-3,4'- imidazolidine]-2'-one from 6-bromo-1'-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2H- spiro[benzofuran-3,4'-imidazolidine]-2',5'-dione instead of 6-bromo-1'-methyl-2H- spiro[benzofuran-3,4'-imidazolidine]-2',5'-dione.
  • Example 701 (3R)-6-[7,7-difluoro-2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-1'-methyl-spiro[2H-benzofuran-3,4'-imidazolidine]- 2'-one
  • Example 702 (3S)-6-[7,7-difluoro-2-[(2S,3R)-3-hydroxy-2-methyl-azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]-1'-methyl-spiro[2H-benzofuran-3,4'-imidazolidine]- 2'-one
  • Isomers were separated by SFC (35% EtOH in CO 2 , CHIRALPAK AD-H, 250 x 21 mm, 60 mL/min).
  • Example 703 6-[7,7-difluoro-2-[(2R)-2-(trifluoromethyl)azetidin-1-yl]-5,6- dihydrocyclopenta[d]pyrimidin-4-yl]spiro[2H-benzofuran-3,5'-imidazolidine]-2',4'-dione
  • 6-bromospiro[2H-benzofuran-3,5'-imidazolidine]-2',4'-dione 250 mg, 0.88 mmol
  • N-ethyl-N-isopropyl-propan-2-amine (0.188 mL, 1.1 mmol
  • 2-(chloromethoxy)ethyl-trimethyl-silane (0.195 mL, 1.1 mmol
  • Example 704 2-[(2S)-2-methylazetidin-1-yl]-4-[1-(oxetan-3-yl)triazol-4-yl]-6,7-dihydro- 5H-cyclopenta[d]pyrimidine The title compound was made according to General Method AB.
  • Example 705 (S)-8-(7,7-difluoro-2-((2S,3R)-3-hydroxy-2-methylazetidin-1-yl)-6,7-dihydro- 5H-cyclopenta[d]pyrimidin-4-yl)-2-(hydroxymethyl)-3,4-dihydrobenzo[f][1,4]oxazepin- 5(2H)-one
  • the title compound was prepared in analogy to General Method Q, using tert-butyl (R)-(3-((tert- butyldimethylsilyl)oxy)-2-hydroxypropyl)carbamate instead of tert-butyl (S)-(1- hydroxypropan-2-yl)carbamate, followed by General Method F using (S)-8-bromo-2- (hydroxymethyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one and 4-chloro-7,7-diflu
  • Example 706 4-(2-(2-cyanoazetidin-1-yl)-7,7-difluoro-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in analogy to General Method B, using 4-(7,7-difluoro-2- (methylsulfonyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide and azetidine-2- carbonitrileoxalic acid salt instead of with 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine and (2S)-2-methylazetidine, respectively.
  • Example 707 (R)-4-(2-(2-cyanoazetidin-1-yl)-7,7-difluoro-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in analogy to General Method B, using 4-(7,7-difluoro-2- (methylsulfonyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide and (2R)- azetidine- 2-carbonitrile oxalic acid salt instead of with 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine and (2S)-2-methylazetidine, respectively.
  • Example 708 4-(2-(3-cyanoazetidin-1-yl)-7,7-difluoro-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)benzamide
  • the title compound was prepared in analogy to General Method B, using 4-(7,7-difluoro-2- (methylsulfonyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)benzamide and azetidine-3- carbonitrile HCl salt instead of 2-chloro-4-(pyridin-3-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine and (2S)-2-methylazetidine, respectively.
  • Example 709 (2R)-1-(7,7-difluoro-4-(3-(S-methylsulfonimidoyl)phenyl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)azetidine-2-carbonitrile
  • the title compound was prepared in analogy to General Method S using (3- bromophenyl)(methyl)sulfane instead of (5-bromo-2-methoxyphenyl)(methyl)sulfane, followed by General Method F using 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H- cyclopenta[d]pyrimidine and tert-butyl ((3-bromophenyl)(methyl)(oxo)- ⁇ 6 - sulfaneylidene)carbamate instead of 4-chloro-2-[(2S)-2-methylazetidin-1-yl]-6,7
  • Example 710 (3-(7,7-difluoro-2-((2S,3R)-3-fluoro-2-methylazetidin-1-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)phenyl)(imino)(methyl)- ⁇ 6 -sulfanone
  • the title compound was prepared in analogy to General Method S using (3- bromophenyl)(methyl)sulfane instead of (5-bromo-2-methoxyphenyl)(methyl)sulfane, followed by General Method F using 4-chloro-7,7-difluoro-2-(methylthio)-6,7-dihydro-5H- cyclopenta[d]pyrimidine and tert-butyl ((3-bromophenyl)(methyl)(oxo)- ⁇ 6 - sulfaneylidene)carbamate instead of 4-chloro-2-[(2S)-2-
  • Example 711 (R)-1-(4-(4-(3-aminooxetan-3-yl)phenyl)-7,7-difluoro-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)azetidine-2-carbonitrile
  • the title compound was prepared in a method analogous to General Method A using 4-chloro- 7,7-difluoro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine and benzyl (3-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-yl)carbamate instead of 2,4-dichloro-6,7- dihydro-5H-cyclopenta[d]pyrimidine and 3-pyridylboronic acid, respectively, followed by General Method M, followed by General Method B using (2R)-azetidine
  • Example 712 (S)-1-(4-(3-(methylsulfonyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin- 2-yl)pyrrolidine-2-carbonitrile
  • (S)-1-(4-(3-(methylsulfonyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2- carboxamide was prepared in analogy to General Method A using 4,4,5,5-tetramethyl-2-(3- (methylsulfonyl)phenyl)-1,3,2-dioxaborolane instead of 3-pyridylboronic acid, followed by General Method B, using 2-chloro-4-(3-(methylsulfonyl)phenyl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine and (S)-pyrrolidine-2-carboxamide instead of 2-chloro-4-(
  • Example 714 2-methyl-1-(4-(3-(methylsulfonyl)phenyl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-2-yl)azetidine-2-carbonitrile 2-methyl-1-(4-(3-(methylsulfonyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2- yl)azetidine-2-carboxylic acid was prepared in analogy to General Method A using 4,4,5,5- tetramethyl-2-(3-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane instead of 3-pyridylboronic acid, followed by General Method B, using 2-chloro-4-(3-(methylsulfonyl)phenyl)-6,7-dihydro-5H- cyclopenta[d]pyrimidine and methyl 2-methylazetidine-2-carboxylate instead of 2-ch

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